Nitrosated and/or nitrosylated cyclooxygenase-2 selective inhibitors, compositions and methods of use

ABSTRACT

The invention describes novel nitrosated and/or nitrosylated cyclooxygenase 2 (COX-2) selective inhibitors and novel compositions comprising at least one nitrosated and/or nitrosylated cyclooxygenase 2 (COX-2) selective inhibitor, and, optionally, at least one compound that donates, transfers or releases nitric oxide, stimulates endogenous synthesis of nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor or is a substrate for nitric oxide synthase, and/or, optionally, at least one therapeutic agent. The invention also provides novel compositions comprising at least one COX-2 selective inhibitor, that is optionally sitrosated and/or nitrosylated, and, optionally, at least one nitric oxide donor and/or at least one therapeutic agent The invention also provides methods for treating inflammation, pain and fever; for treating and/or improving the gastrointestinal properties of COX-2 selective inhibitors; for facilitating wound healing; for treating and/or preventing renal and/or respiratory toxicity; for treating and/or preventing other disorders resulting from elevated levels of cyclooxygenase-2; and for improving the cardiovascular profile of COX-2 selective inhibitors. The invention also provides novel kits comprising at least one COX-2 selective inhibitor optionally nitrosated and/or nitrosylated, and, optionally, at least one nitric oxide donor, and/or, optionally, at least one therapeutic agent. The novel cyclooxygenase 2 selective inhibitors of the invention are preferably 2(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetic acid and nitrosated derivatives thereof.

RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional ApplicationNo. 60/387,433 filed June 11, 2002.

FIELD OF THE INVENTION

[0002] The invention describes novel nitrosated and/or nitrosylatedcyclooxygenase 2 (COX-2) selective inhibitors and novel compositionscomprising at least one nitrosated and/or nitrosylated cyclooxygenase 2(COX-2) selective inhibitor, and, optionally, at least one compound thatdonates, transfers or releases nitric oxide, stimulates endogenoussynthesis of nitric oxide, elevates endogenous levels ofendothelium-derived relaxing factor or is a substrate for nitric oxidesynthase, and/or at least one therapeutic agent. The invention alsoprovides novel compositions comprising at least one COX-2 selectiveinhibitor, that is optionally nitrosated and/or nitrosylated, and atleast one compound that donates, transfers or releases nitric oxide,elevates endogenous levels of endothelium-derived relaxing factor,stimulates endogenous synthesis of nitric oxide or is a substrate fornitric oxide synthase and/or at least one therapeutic agent. Theinvention also provides novel kits comprising at least one COX-2selective inhibitor, that is optionally nitrosated and/or nitrosylated,and, optionally, at least one nitric oxide donor and/or at least onetherapeutic agent. The invention also provides methods for treatinginflammation, pain and fever; for treating and/or improving thegastrointestinal properties of COX-2 selective inhibitors; forfacilitating wound healing; for treating and/or preventing renal and/orrespiratory toxicities; for treating and/or preventing other disordersresulting from elevated levels of cyclooxygenase-2; and for improvingthe cardiovascular profile of COX-2 selective inhibitors. The novelnitrosated cyclooxygenase 2 selective inhibitors of the invention arepreferably nitrosated derivatives of2(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetic acid.

BACKGROUND OF THE INVENTION

[0003] Nonsteroidal anti-inflammatory compounds (NSAIDs) are widely usedfor the treatment of pain, inflammation, and acute and chronicinflammatory disorders such as osteoarthritis and rheumatoid arthritis.These compounds inhibit the activity of the enzyme cyclooxygenase (COX),also known as prostaglandin G/H synthase, which is the enzyme thatconverts arachidonic acid into prostanoids. The NSAIDs also inhibit theproduction of other prostaglandins, especially prostaglandin G₂,prostaglandin H₂ and prostaglandin E₂, thereby reducing theprostaglandin-induced pain and swelling associated with the inflammationprocess. The chronic use of NSAIDs has been associated with adverseeffects, such as gastrointestinal ulceration and renal toxicity. Theundesirable side effects are also due to the inhibition of prostaglandinin the affected organ.

[0004] Recently two isoforms of cyclooxygenase, encoded by two distinctgenes (Kujubu et al, J. Biol. Chem., 266, 12866-12872 (1991)), have beenidentified—a constitutive form, cyclooxygenase-1 (COX-1), and aninductive form, cyclooxygenase-2 (COX-2). It is thought that theantiinflammatory effects of NSAIDs are mediated by the inhibition ofCOX-2, whereas the side effects seem to be caused by the inhibition ofCOX-1. The NSAIDs currently on the market either inhibit both isoformsof COX with little selectivity for either isoform or are COX-1selective. Recently compounds that are COX-2 selective inhibitors havebeen developed and marketed. These COX-2 selective inhibitors have thedesired therapeutic profile of an antiinflammatory drug without theadverse effects commonly associated with the inhibition of COX-1.However, these compounds can result in dyspepsia and can causegastropathy (Mohammed et al, N. Engl. J. Med., 340(25) 2005 (1999)).Additionally the COX-2 selective inhibitors can increase the risk ofcardiovascular events in a patient (Mukherjee et al., JAMA 286(8)954-959 (2001)); Hennan et al., Circulation, 104:820-825 (2001)).

[0005] There is still a need in the art for novel COX-2 selectiveinhibitor compounds that have gastroprotective properties, facilitatewound healing, decreased renal and/or respiratory toxicity anddyspepsia, improved cardiovascular profile and that can be used at lowdosages. The invention is directed to these, as well as other, importantends.

SUMMARY OF THE INVENTION

[0006] The invention provides novel nitrosated and/or nitrosylatedderivatives of COX-2 selective inhibitors, or a pharmaceuticallyacceptable salt thereof. These compounds are potent analgesics, haveantiinflammatory properties and have an unexpected potential forfacilitating wound healing. The novel compounds also have unexpectedproperties in the treatment and/or prevention of renal and/orrespiratory toxicity and for improving the cardiovascular profile ofCOX-2 selective inhibitors. The COX-2 selective inhibitor, or apharmaceutically acceptable salt thereof, can be nitrosated and/ornitrosylated through one or more sites, such as oxygen (hydroxylcondensation), sulfur (sulfhydryl condensation) and/or nitrogen. Theinvention also provides compositions comprising the novel compoundsdescribed herein in a pharmaceutically acceptable carrier.

[0007] The invention is also based on the discovery that administeringat least one parent COX-2 selective inhibitor, and, optionally, at leastone nitric oxide donor reduces the gastrointestinal distress induced byCOX-2 selective inhibitors. Nitric oxide donors include, for example,S-nitrosothiols, nitrites, nitrates, N-oxo-N-nitrosamines, SPM 3672, SPM5185, SPM 5186 and analogues thereof, and substrates of the variousisozymes of nitric oxide synthase. Thus, another aspect of the inventionprovides compositions comprising at least one parent COX-2 selectiveinhibitor and at least one compound that donates, transfers or releasesnitric oxide as a charged species, i.e., nitrosonium (NO+) or nitroxyl(NO−), or as the neutral species, nitric oxide (NO•), and/or stimulatesendogenous production of nitric oxide or EDRF in vivo and/or is asubstrate for nitric oxide synthase. The invention also provides forsuch compositions in a pharmaceutically acceptable carrier.

[0008] Yet another aspect of the invention provides compositionscomprising at least one COX-2 selective inhibitor, that is optionallysubstituted with at least one NO₂ group and/or at least one NO group(i.e., nitrosated and/or nitrosylated respectively), and, optionally, atleast one compound that donates, transfers or releases nitric oxide as acharged species, i.e., nitrosonium (NO⁺) or nitroxyl (NO−), or as theneutral species, nitric oxide (NO•), and/or stimulates endogenousproduction of nitric oxide or EDRF in vivo and/or is a substrate fornitric oxide synthase, and/or, optionally, at least one therapeuticagent, including but not limited to, steroids, nonsteroidalantiinflammatory compounds (NSAID), 5-lipoxygenase (5-LO) inhibitors,leukotriene B₄ (LTB₄) receptor antagonists, leukotriene A₄ (LTA₄)hydrolase inhibitors, 5-HT agonists, HMG CoA inhibitors, H₂ antagonists,antineoplastic agents, antiplatelet agents, thrombin inhibitors,thromboxane inhibitors, decongestants, diuretics, sedating ornon-sedating anti-histamines, inducible nitric oxide synthaseinhibitors, opioids, analgesics, Helicobacter pylori inhibitors, protonpump inhibitors, isoprostane inhibitors, and the like. The inventionalso provides for such compositions in a pharmaceutically acceptablecarrier.

[0009] Yet another aspect of the present invention provides methods fortreating and/or preventing inflammation, pain and fever; for treatingand/or improving gastrointestinal properties of COX-2 inhibitors; forfacilitating wound healing; for treating and/or preventing renal and/orrespiratory toxicity; and for treating and/or preventing COX-2 mediateddisorders (i.e., disorders resulting from elevated levels of COX-2) in apatient in need thereof which comprises administering to the patient atherapeutically effective amount of at least one COX-2 selectiveinhibitor, that is optionally substituted with at least one NO₂ groupand/or at least one NO group (i.e., nitrosated and/or nitrosylatedrespectively), and, optionally, at least one compound that donates,transfers or releases nitric oxide as a charged species, i.e.,nitrosonium (NO⁺) or nitroxyl (NO−), or as the neutral species, nitricoxide (NO•), and/or stimulates endogenous production of nitric oxide orEDRF in vivo and/or is a substrate for nitric oxide synthase and/orstimulates endogenous production of NO or EDRF in vivo and/or is asubstrate for nitric oxide synthase (i.e., NO donors). The methods canoptionally further comprise the administration of at least onetherapeutic agent, such as, for example, steroids, nonsteroidalantiinflammatory compounds (NSAID), 5-lipoxygenase (5-LO) inhibitors,leukotriene B₄ (LTB₄) receptor antagonists, leukotriene A₄ (LTA₄)hydrolase inhibitors, 5-HT agonists, HMG CoA inhibitors, H₂ antagonists,antineoplastic agents, antiplatelet agents, thrombin inhibitors,thromboxane inhibitors, decongestants, diuretics, sedating ornon-sedating anti-histamines, inducible nitric oxide synthaseinhibitors, opioids, analgesics, Helicobacter pylori inhibitors, protonpump inhibitors, isoprostane inhibitors, and mixtures of two or morethereof. In this aspect of the invention, the methods can involveadministering the COX-2 selective inhibitors, that are optionallynitrosated and/or nitrosyalted, administering the COX-2 selectiveinhibitors, that are optionally nitrosated and/or nitrosylated and NOdonors, administering the COX-2 selective inhibitors, that areoptionally nitrosated and/or nitrosylated, and therapeutic agents, oradministering the COX-2 selective inhibitors, that are optionallynitrosated and/or nitrosylated, NO donors and therapeutic agents. Theselective COX-2 inhibitors, nitric oxide donors, and/or therapeuticagents can be administered separately or as components of the samecomposition in one or more pharmaceutically acceptable carriers.

[0010] Yet another aspect of the invention provides methods forimproving the cardiovascular profile of COX-2 selective inhibitors in apatient in need thereof which comprises administering to the patient atherapeutically effective amount of at least one COX-2 selectiveinhibitor, optionally substituted with at least one NO₂ and/or NO group(i.e. nitrosated and/or nitrosylated), and, optionally, at least onecompound that donates, transfers or releases nitric oxide as a chargedspecies, i.e., nitrosonium (NO⁺) or nitroxyl (NO−), or as the neutralspecies, nitric oxide (NO•), and/or stimulates endogenous production ofnitric oxide or EDRF in vivo and/or is a substrate for nitric oxidesynthase and/or stimulates endogenous production of NO or EDRF in vivoand/or is a substrate for nitric oxide synthase (i.e. NO donor). Themethods can optionally further comprise the administration of at leastone of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors,antiplatelet agents, thrombin inhibitors, thromboxane inhibitors, andmixtures of two or more thereof. In this aspect of the invention, themethods can involve administering the nitrosated and/or nitrosylatedCOX-2 selective inhibitors, administering the COX-2 selectiveinhibitors, that are optionally nitrosated and/or nitrosylated, and NOdonors, administering the COX-2 selective inhibitors, that areoptionally nitrosated and/or nitrosylated, and at least one of3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors, antiplateletagents, thrombin inhibitors or thromboxane inhibitors, or administeringthe COX-2 selective inhibitors, that are optionally nitrosated and/ornitrosylated, NO donors, and at least one of 3-hydroxy-3methylglutarylcoenzyme A (HMG-CoA) inhibitors, antiplatelet agents, thrombininhibitors or thromboxane inhibitors. The COX-2 inhibitors, nitric oxidedonors, and/or 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA)inhibitors, antiplatelet agents, thrombin inhibitors or thromboxaneinhibitors can be administered separately or as components of the samecomposition in one or more pharmaceutically acceptable carriers.

[0011] In yet another aspect the invention provides kits comprising atleast one COX-2 selective inhibitor, that is optionally substituted atleast one NO₂ group and/or at least one NO group (i.e., nitrosatedand/or nitrosylated respectively), and, optionally, at least onecompound that donates, transfers or releases nitric oxide as a chargedspecies, i.e., nitrosonium (NO⁺) or nitroxyl (NO−), or as the neutralspecies, nitric oxide (NO•), and/or stimulates endogenous production ofnitric oxide or EDRF in vivo and/or is a substrate for nitric oxidesynthase. The kit can further comprise at least one therapeutic agent,such as, for example, steroids, nonsteroidal antiinflammatory compounds(NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B₄ (LTB₄)receptor antagonists, leukotriene A₄ (LTA₄) hydrolase inhibitors, 5-HTagonists, 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) inhibitors, H₂antagonists, antineoplastic agents, antiplatelet agents, thrombininhibitors, thromboxane inhibitors, decongestants, diuretics, sedatingor non-sedating anti-histamines, inducible nitric oxide synthaseinhibitors, opioids, analgesics, Helicobacter pylori inhibitors, protonpump inhibitors, isoprostane inhibitors, and mixtures of two or morethereof. The COX-2 selective inhibitor, the nitric oxide donor and/ortherapeutic agent, can be separate components in the kit or can be inthe form of a composition in one or more pharmaceutically acceptablecarriers.

DETAILED DESCRIPTION OF THE INVENTION

[0012] As used throughout the disclosure, the following terms, unlessotherwise indicated, shall be understood to have the following meanings.

[0013] “NSAID” refers to a nonsteroidal anti-inflammatory compound or anonsteroidal anti-inflammatory drug. NSAIDs inhibit cyclooxygenase, theenzyme responsible for the biosyntheses of the prostaglandins andcertain autocoid inhibitors, including inhibitors of the variousisozymes of cyclooxygenase (including but not limited tocyclooxygenase-1 and -2), and as inhibitors of both cyclooxygenase andlipoxygenase.

[0014] “Cyclooxygenase-2 (COX-2) selective inhibitor” refers to acompound that selectively inhibits the cyclooxygenase-2 enzyme over thecyclooxygenase-1 enzyme. In one embodiment, the compound has acyclooxygenase-2 IC₅₀ of less than about 2 μM and a cyclooxygenase-1IC₅₀ of greater than about 5 μM, in the human whole blood COX-2 assay(as described in Brideau et al., Inflamm Res., 45: 68-74 (1996)) andalso has a selectivity ratio of cyclooxygenase-2 inhibition overcyclooxygenase-1 inhibition of at least 10, and preferably of at least40. In another embodiment, the compound has a cyclooxygenase-1 IC₅₀ ofgreater than about 1 μM, and preferably of greater than 20 μM. Thecompound can also inhibit the enzyme, lipoxygenase. Such selectivity mayindicate an ability to reduce the incidence of common NSAID-induced sideeffects.

[0015] “Parent COX-2 inhibitor” refers to a non-nitrosated and/ornon-nitrosylated COX-2 inhibitor, or pharmaceutically acceptable saltsthereof or pharmaceutically acceptable esters thereof. “Parent COX-2inhibitor” includes the compounds of Formula (I) before they arenitrosated and/or nitrosylated by the methods described herein.

[0016] “Therapeutic agent” includes any therapeutic agent that can beused to treat or prevent the diseases described herein. “Therapeuticagents” include, for example, steroids, nonsteroidal anti-inflammatorycompounds, 5-lipoxygenase inhibitors, leukotriene B₄ receptorantagonists, leukotriene A₄ hydrolase inhibitors,3-hydroxy-3-methylglutaryl coenzyme A inhibitors, H₂ antagonists,antineoplastic agents, antiplatelet agents, thrombin inhibitors,thromboxane inhibitors, decongestants, diuretics, sedating ornon-sedating anti-histamines, inducible nitric oxide synthaseinhibitors, opioids, analgesics, Helicobacter pylori inhibitors, protonpump inhibitors, isoprostane inhibitors, and the like. Therapeutic agentincludes the pro-drugs and pharmaceutical derivatives thereof includingbut not limited to the corresponding nitrosated and/or nitrosylatedderivatives. Although nitric oxide donors have therapeutic activity, theterm “therapeutic agent” does not include the nitric oxide donorsdescribed herein, since nitric oxide donors are separately defined.

[0017] “Cardiovascular disease or disorder” refers to any cardiovasculardisease or disorder known in the art, including, but not limited to,restenosis, atherosclerosis, atherogenesis, angina, (particularlychronic, stable angina pectoris), ischemic disease, congestive heartfailure or pulmonary edema associated with acute myocardial infarction,thrombosis, controlling blood pressure in hypertension (especiallyhypertension associated with cardiovascular surgical procedures),thromboemboembolic events, platelet aggregation, platelet adhesion,smooth muscle cell proliferation, vascular complications associated withthe use of medical devices, wounds associated with the use of medicaldevices, cerebrovascular ischemic events, and the like. Complicationsassociated with the use of medical devices may occur as a result ofincreased platelet deposition, activation, thrombus formation orconsumption of platelets and coagulation proteins. Such complications,which are within the definition of “cardiovascular disease or disorder,”include, for example, myocardial infarction, ischemic stroke, transientischemic stroke, thromboemboembolic events, pulmonary thromboembolism,cerebral thromboembolism, thrombophlebitis, thrombocytopenia, bleedingdisorders and/or any other complications which occur either directly orindirectly as a result of the foregoing disorders.

[0018] “Restenosis” is a cardiovascular disease or disorder that refersto the closure of a peripheral or coronary artery following trauma tothe artery caused by an injury such as, for example, angioplasty,balloon dilation, atherectomy, laser ablation treatment or stentinsertion. Restenosis can also occur following a number of invasivesurgical techniques, such as, for example, transplant surgery, veingrafting, coronary artery bypass surgery, endarterectomy, hearttransplantation, balloon angioplasty, atherectomy, laser ablation,endovascular stenting, and the like.

[0019] “Atherosclerosis” is a form of chronic vascular injury in whichsome of the normal vascular smooth muscle cells in the artery wall,which ordinarily control vascular tone regulating blood flow, changetheir nature and develop “cancer-like” behavior. These vascular smoothmuscle cells become abnormally proliferative, secreting substances suchas growth factors, tissue-degradation enzymes and other proteins, whichenable them to invade and spread into the inner vessel lining, blockingblood flow and making that vessel abnormally susceptible to beingcompletely blocked by local blood clotting, resulting in the death ofthe tissue served by that artery. Atherosclerotic cardiovasculardisease, coronary heart disease (also known as coronary artery diseaseor ischemic heart disease), cerebrovascular disease and peripheralvessel disease are all common manifestations of atherosclerosis and aretherefore encompassed by the terms “atherosclerosis” and“atherosclerotic disease”.

[0020] “Improving the cardiovascular profile” refers to and includesreducing the risk of thromboembolic events, reducing the risk ofdeveloping atherosclerosis and atherosclerotic diseases, and inhibitingplatelet aggregation of the parent COX-2 inhibitor.

[0021] “Thromboemboembolic events” includes, but is not limited to,ischemic stroke, transient ischemic stroke, myocardial infarction,angina pectoris, thrombosis, thromboembolism, thrombotic occlusion andreocclusion, acute vascular events, restenosis, transient ischemicattacks, and first and subsequent thrombotic stroke. Patients who are atrisk of developing thromboembolic events, may include those with afamilial history of, or genetically predisposed to, thromboembolicdisorders, who have had ischemic stroke, transient ischemic stroke,myocardial infarction, and those with unstable angina pectoris orchronic stable angina pectoris and patients with alteredprostacyclin/thromboxane A₂ homeostasis or higher than normalthromboxane A₂ levels leading to increase risk for thromboembolism,including patients with diabetes and rheumatoid arthritis.

[0022] “Thromboxane inhibitor” refers to any compound that reversibly orirreversibly inhibits thromboxane synthesis, and includes compoundswhich are the so-called thromboxane A₂ receptor antagonists, thromboxaneA₂ antagonists, thromboxane A₂/prostaglandin endoperoxide antagonists,thromboxane receptor (TP) antagonists, thromboxane antagonists,thromboxane synthase inhibitors, and dual acting thromboxane synthaseinhibitors and thromboxane receptor antagonists. The characteristics ofthe preferred thromboxane inhibitor should include the suppression ofthromboxane A₂ formation (thromboxane synthase inhibitors) and/orblockade of thromboxane A₂ and prostaglandin H₂ platelet and vessel wall(thromboxane receptor antagonists). The effects should block plateletactivation and therefore platelet function.

[0023] “Thromboxane A₂ receptor antagonist” refers to any compound thatreversibly or irreversibly blocks the activation of any thromboxane A₂receptor.

[0024] “Thromboxane synthase inhibitor” refers to any compound thatreversibly or irreversibly inhibits the enzyme thromboxane synthesisthereby reducing the formation of thromboxane A₂. Thromboxane synthaseinhibitors may also increase the synthesis of antiaggregatoryprostaglandins including prostacyclin and prostaglandin D₂. ThromboxaneA₂ receptor antagonists and thromboxane synthase inhibitors and can beidentified using the assays described in Tai, Methods of Enzymology,Vol. 86, 110-113 (1982); Hall, Medicinal Research Reviews, 11:503-579(1991) and Coleman et al., Pharmacol Rev., 46: 205-229 (1994) andreferences therein, the disclosures of which are incorporated herein byreference in its entirety.

[0025] “Dual acting thromboxane receptor antagonist and thromboxanesynthase inhibitor” refers to any compound that simultaneously acts as athromboxane A₂ receptor antagonist and a thromboxane synthase inhibitor.

[0026] “Thrombin inhibitors” refers to and includes compounds thatinhibit hydrolytic activity of thrombin, including the catalyticconversion of fibrinogen to fibrin, activation of Factor V to Va, FactorVIII to VIIIa, Factor XIII to XIIIa and platelet activation. Thrombininhibitors may be identified using assays described in Lewis et at.,Thrombosis Research. 70: 173-190 (1993).

[0027] “Platelet aggregation” refers to the binding of one or moreplatelets to each other. Platelet aggregation is commonly referred to inthe context of generalized atherosclerosis, not with respect to plateletadhesion on vasculature damaged as a result of physical injury during amedical procedure. Platelet aggregation requires platelet activationwhich depends on the interaction between the ligand and its specificplatelet surface receptor.

[0028] “Platelet activation” refers either to the change in conformation(shape) of a cell, expression of cell surface proteins (e.g., theIIb/IIIa receptor complex, loss of GPIb surface protein), and secretionof platelet derived factors (e.g., serotonin, growth factors).

[0029] “Patient” refers to animals, preferably mammals, most preferablyhumans, and includes males and females, and children and adults.

[0030] “Therapeutically effective amount” refers to the amount of thecompound and/or composition that is effective to achieve its intendedpurpose.

[0031] “Transdermal” refers to the delivery of a compound by passagethrough the skin and into the blood stream.

[0032] “Transmucosal” refers to delivery of a compound by passage of thecompound through the mucosal tissue and into the blood stream.

[0033] “Penetration enhancement” or “permeation enhancement” refers toan increase in the permeability of the skin or mucosal tissue to aselected pharmacologically active compound such that the rate at whichthe compound permeates through the skin or mucosal tissue is increased.

[0034] “Carriers” or “vehicles” refers to carrier materials suitable forcompound administration and include any such material known in the artsuch as, for example, any liquid, gel, solvent, liquid diluent,solubilizer, or the like, which is non-toxic and which does not interactwith any components of the composition in a deleterious manner.

[0035] “Nitric oxide adduct” or “NO adduct” refers to compounds andfunctional groups which, under physiological conditions, can donate,release and/or directly or indirectly transfer any of the three redoxforms of nitrogen monoxide (NO⁺, NO⁻, NO∘), such that the biologicalactivity of the nitrogen monoxide species is expressed at the intendedsite of action.

[0036] “Nitric oxide releasing” or “nitric oxide donating” refers tomethods of donating, releasing and/or directly or indirectlytransferring any of the three redox forms of nitrogen monoxide (NO⁺,NO⁻, NO∘), such that the biological activity of the nitrogen monoxidespecies is expressed at the intended site of action.

[0037] “Nitric oxide donor” or “NO donor” refers to compounds thatdonate, release and/or directly or indirectly transfer a nitrogenmonoxide species, and/or stimulate the endogenous production of nitricoxide or endothelium-derived relaxing factor (EDRF) in vivo and/orelevate endogenous levels of nitric oxide or EDRF in vivo. “NO donor”also includes compounds that are substrates for nitric oxide synthase.

[0038] “Alkyl” refers to a lower alkyl group, a haloalkyl group, ahydroxyalkyl group, an alkenyl group, an alkynyl group, a bridgedcycloalkyl group, a cycloalkyl group or a heterocyclic ring, as definedherein. An alkyl group may also comprise one or more radical species,such as, for example a cycloalkylalkyl group or a heterocyclicalkylgroup.

[0039] “Lower alkyl” refers to branched or straight chain acyclic alkylgroup comprising one to about ten carbon atoms (preferably one to abouteight carbon atoms, more preferably one to about six carbon atoms).Exemplary lower alkyl groups include methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, neopentyl, iso-amyl,hexyl, octyl, and the like.

[0040] “Substituted lower alkyl” refers to a lower alkyl group, asdefined herein, wherein one or more of the hydrogen atoms have beenreplaced with one or more R¹⁰⁰ groups, wherein each R¹⁰⁰ isindependently a hydroxy, an oxo, a carboxyl, a carboxamido, a halo, acyano or an amino group, as defined herein.

[0041] “Haloalkyl” refers to a lower alkyl group, an alkenyl group, analkynyl group, a bridged cycloalkyl group, a cycloalkyl group or aheterocyclic ring, as defined herein, to which is appended one or morehalogens, as defined herein. Exemplary haloalkyl groups includetrifluoromethyl, chloromethyl, 2-bromobutyl, 1-bromo-2-chloro-pentyl,and the like.

[0042] “Alkenyl” refers to a branched or straight chain C₂-C₁₀hydrocarbon (preferably a C₂-C₈ hydrocarbon, more preferably a C₂-C₆hydrocarbon) that can comprise one or more carbon-carbon double bonds.Exemplary alkenyl groups include propylenyl, buten-1-yl, isobutenyl,penten-1-yl, 2,2-methylbuten-1-yl, 3-methylbuten-1-yl, hexan-1-yl,hepten-1-yl, octen-1-yl, and the like.

[0043] “Lower alkenyl” refers to a branched or straight chain C₂-C₄hydrocarbon that can comprise one or two carbon-carbon double bonds.

[0044] “Substituted alkenyl” refers to a branched or straight chainC₂-C₁₀ hydrocarbon (preferably a C₂-C₈ hydrocarbon, more preferably aC₂-C₆ hydrocarbon) which can comprise one or more carbon-carbon doublebonds, wherein one or more of the hydrogen atoms have been replaced withone or more R¹⁰⁰ groups, wherein each R¹⁰⁰ is independently a hydroxy,an oxo, a carboxyl, a carboxamido, a halo, a cyano or an amino group, asdefined herein.

[0045] “Alkynyl” refers to an unsaturated acyclic C₂-C₁₀ hydrocarbon(preferably a C₂-C₈ hydrocarbon, more preferably a C₂-C₆ hydrocarbon)that can comprise one or more carbon-carbon triple bonds. Exemplaryalkynyl groups include ethynyl, propynyl, butyn-1-yl, butyn-2yl,pentyl-1-yl, pentyl-2-yl, 3-methylbutyn-1-yl, hexyl-1-yl, hexyl-2-yl,hexyl-3-yl, 3,3-dimethylbutyn-1-yl, and the like.

[0046] “Bridged cycloalkyl” refers to two or more cycloalkyl groups,heterocyclic groups, or a combination thereof fused via adjacent ornon-adjacent atoms. Bridged cycloalkyl groups can be unsubstituted orsubstituted with one, two or three substituents independently selectedfrom alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo,carboxyl, alkylcarboxylic acid, aryl, amidyl, ester, alkylcarboxylicester, carboxamido, alkylcarboxamido, oxo and nitro. Exemplary bridgedcycloalkyl groups include adamantyl, decahydronapthyl, quinuclidyl,2,6-dioxabicyclo(3.3.0)octane, 7-oxabycyclo(2.2. 1)heptyl,8-azabicyclo(3,2, 1)oct-2-enyl and the like.

[0047] “Cycloalkyl” refers to a saturated or unsaturated cyclichydrocarbon comprising from about 3 to about 10 carbon atoms. Cycloalkylgroups can be unsubstituted or substituted with one, two or threesubstituents independently selected from alkyl, alkoxy, amino,alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, aryl,amidyl, ester, hydroxy, halo, carboxyl, alkylcarboxylic acid,alkylcarboxylic ester, carboxamido, alkylcarboxamido, oxo,alkylsulfinyl, and nitro. Exemplary cycloalkyl groups includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl,cyclohepta-1,3-dienyl, and the like.

[0048] “Heterocyclic ring or group” refers to a saturated or unsaturatedcyclic hydrocarbon group having about 2 to about 10 carbon atoms(preferably about 4 to about 6 carbon atoms) where 1 to about 4 carbonatoms are replaced by one or more nitrogen, oxygen and/or sulfur atoms.Sulfur maybe in the thio, sulfinyl or sulfonyl oxidation state. Theheterocyclic ring or group can be fused to an aromatic hydrocarbongroup. Heterocyclic groups can be unsubstituted or substituted with one,two or three substituents independently selected from alkyl, alkoxy,amino, alkylthio, aryloxy, arylthio, arylalkyl, hydroxy, oxo, thial,halo, carboxyl, carboxylic ester, alkylcarboxylic acid, alkylcarboxylicester, aryl, arylcarboxylic acid, arylcarboxylic ester, amidyl, ester,alkylcarbonyl, arylcarbonyl, alkylsulfinyl, carboxamido,alkylcarboxamido, arylcarboxamido, sulfonic acid, sulfonic ester,sulfonamido and nitro. Exemplary heterocyclic groups include pyrrolyl,furyl, thienyl, 3-pyrrolinyl,4,5,6-trihydro-2H-pyranyl, pyridinyl,1,4dihydropyridinyl, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl,oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl, furanyl,tetrhydrofuranyl, tetrazolyl, pyrrolinyl, pyrrolindinyl, oxazolindinyl1,3-dioxolanyl, imidazolinyl, imidazolindinyl, pyrazolinyl,pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl,1,2,3-triazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4H-pyranyl,piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl,pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl,benzo(b)thiophenyl, benzimidazolyl, benzothiazolinyl, quinolinyl, andthe like.

[0049] “Heterocyclic compounds” refer to mono- and polycyclic compoundscomprising at least one aryl or heterocyclic ring.

[0050] “Aryl” refers to a monocyclic, bicyclic, carbocyclic orheterocyclic ring system comprising one or two aromatic rings. Exemplaryaryl groups include phenyl, pyridyl, napthyl, quinoyl,tetrahydronaphthyl, furanyl, indanyl, indenyl, indoyl, and the like.Aryl groups (including bicyclic aryl groups) can be unsubstituted orsubstituted with one, two or three substituents independently selectedfrom alkyl, alkoxy, alkylthio, amino, alkylamino, dialkylamino,arylamino, diarylamino, alkylarylamino, halo, cyano, alkylsulfinyl,hydroxy, carboxyl, carboxylic ester, alkylcarboxylic acid,alkylcarboxylic ester, aryl, arylcarboxylic acid, arylcarboxylic ester,alkylcarbonyl, arylcarbonyl, amidyl, ester, carboxamido,alkylcarboxamido, carbomyl, sulfonic acid, sulfonic ester, sulfonamidoand nitro. Exemplary substituted aryl groups include tetrafluorophenyl,pentafluorophenyl, sulfonamide, alkylsulfonyl, arylsulfonyl, and thelike.

[0051] “Cycloalkenyl” refers to an unsaturated cyclic C₂-C₁₀ hydrocarbon(preferably a C₂-C₈ hydrocarbon, more preferably a C₂-C₆ hydrocarbon)which can comprise one or more carbon-carbon triple bonds.

[0052] “Alkylaryl” refers to an alkyl group, as defined herein, to whichis appended an aryl group, as defined herein. Exemplary alkylaryl groupsinclude benzyl, phenylethyl, hydroxybenzyl, fluorobenzyl,fluorophenylethyl, and the like.

[0053] “Arylalkyl” refers to an aryl radical, as defined herein,attached to an alkyl radical, as defined herein. Exemplary arylalkylgroups include benzyl, phenylethyl, 4-hydroxybenzyl, 3fluorobenzyl,2-fluorophenylethyl, and the like.

[0054] “Arylalkenyl” refers to an aryl radical, as defined herein,attached to an alkenyl radical, as defined herein. Exemplary arylalkenylgroups include styryl, propenylphenyl, and the like.

[0055] “Cycloalkylalkyl” refers to a cycloalkyl radical, as definedherein, attached to an alkyl radical, as defined herein.

[0056] “Cycloalkylalkoxy” refers to a cycloalkyl radical, as definedherein, attached to an alkoxy radical, as defined herein.

[0057] “Cycloalkylalkylthio” refers to a cycloalkyl radical, as definedherein, attached to an alkylthio radical, as defined herein.

[0058] “Heterocyclicalkyl” refers to a heterocyclic ring radical, asdefined herein, attached to an alkyl radical, as defined herein.

[0059] “Arylheterocyclic ring” refers to a bi- or tricyclic ringcomprised of an aryl ring, as defined herein, appended via two adjacentcarbon atoms of the aryl ring to a heterocyclic ring, as defined herein.Exemplary arylheterocyclic rings include dihydroindole,1,2,3,4-tetra-hydroquinoline, and the like.

[0060] “Alkoxy” refers to R₅₀O-, wherein R₅₀ is an alkyl group, asdefined herein (preferably a lower alkyl group or a haloalkyl group, asdefined herein). Exemplary alkoxy groups include methoxy, ethoxy,t-butoxy, cyclopentyloxy, trifluoromethoxy, and the like.

[0061] “Aryloxy” refers to R₅₅O-, wherein R₅₅ is an aryl group, asdefined herein. Exemplary arylkoxy groups include napthyloxy,quinolyloxy, isoquinolizinyloxy, and the like.

[0062] “Alkylthio” refers to R₅₀S-, wherein R₅₀ is an alkyl group, asdefined herein.

[0063] “Lower alkylthio” refers to a lower alkyl group, as definedherein, appended to a thio group, as defined herein.

[0064] “Arylalkoxy” or “alkoxyaryl” refers to an alkoxy group, asdefined herein, to which is appended an aryl group, as defined herein.Exemplary arylalkoxy groups include benzyloxy, phenylethoxy,chlorophenylethoxy, and the like.

[0065] “Alkoxyalkyl” refers to an alkoxy group, as defined herein,appended to an alkyl group, as defined herein. Exemplary alkoxyalkylgroups include methoxymethyl, methoxyethyl, isopropoxymethyl, and thelike.

[0066] “Alkoxyhaloalkyl” refers to an alkoxy group, as defined herein,appended to a haloalkyl group, as defined herein. Exemplaryalkoxyhaloalkyl groups include 4- methoxy-2-chlorobutyl and the like.

[0067] “Cycloalkoxy” refers to R₅₄O-, wherein R₅₄ is a cycloalkyl groupor a bridged cycloalkyl group, as defined herein. Exemplary cycloalkoxygroups include cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, and thelike.

[0068] “Cycloalkylthio” refers to R₅₄S-, wherein R₅₄ is a cycloalkylgroup or a bridged cycloalkyl group, as defined herein. Exemplarycycloalkylthio groups include cyclopropylthio, cyclopentylthio,cyclohexylthio, and the like.

[0069] “Haloalkoxy” refers to an alkoxy group, as defined herein, inwhich one or more of the hydrogen atoms on the alkoxy group aresubstituted with halogens, as defined herein. Exemplary haloalkoxygroups include 1,1,1-trichloroethoxy, 2-bromobutoxy, and the like.

[0070] “Hydroxy” refers to —OH.

[0071] “Oxo” refers to ═O.

[0072] “Oxy” refers to —O⁻R₇₇ ⁺ wherein R₇₇ is an organic or inorganiccation.

[0073] “Oxime” refers to (═N—OR₈₁) wherein R₈₁ is a hydrogen, an alkylgroup, an aryl group, an alkylsulfonyl group, an arylsulfonyl group, acarboxylic ester, an alkylcarbonyl group, an arylcarbonyl group, acarboxamido group, an alkoxyalkyl group or an alkoxyaryl group.

[0074] “Hydrazone refers to (═N—N(R₈₁)(R′₈₁)) wherein R′₈₁ isindependently selected from R₈₁, and R₈₁ is as defined herein.

[0075] “Organic cation” refers to a positively charged organic ion.Exemplary organic cations include alkyl substituted ammonium cations,and the like.

[0076] “Inorganic cation” refers to a positively charged metal ion.Exemplary inorganic cations include Group I metal cations such as forexample, sodium, potassium, and the like.

[0077] “Hydroxyalkyl” refers to a hydroxy group, as defined herein,appended to an alkyl group, as defined herein.

[0078] “Nitrate” refers to —O—NO₂.

[0079] “Nitrite” refers to —O—NO.

[0080] “Thionitrate” refers to —S—NO₂.

[0081] “Thionitrite” and “nitrosothiol” refer to —S—NO.

[0082] “Nitro” refers to the group —NO₂ and “nitrosated” refers tocompounds that have been substituted therewith.

[0083] “Nitroso” refers to the group —NO and “nitrosylated” refers tocompounds that have been substituted therewith.

[0084] “Nitrile” and “cyano” refer to —CN.

[0085] “Halogen” or “halo” refers to iodine (I), bromine (Br), chlorine(Cl), and/or fluorine (F).

[0086] “Amino” refers to —NH₂, an alkylamino group, a dialkylaminogroup, an arylamino group, a diarylamino group, an alkylarylamino groupor a heterocyclic ring, as defined herein.

[0087] “Alkylamino” refers to R₅₀NH—, wherein R₅₀ is an alkyl group, asdefined herein. Exemplary alkylamino groups include methylamino,ethylamino, butylamino, cyclohexylamino, and the like.

[0088] “Arylamino” refers to R₅₅NH—, wherein R₅₅ is an aryl group, asdefined herein.

[0089] “Dialkylamino” refers to R₅₂R₅₃N—, wherein R₅₂ and R₅₃ are eachindependently an alkyl group, as defined herein. Exemplary dialkylaminogroups include dimethylamino, diethylamino, methyl propargylamino, andthe like.

[0090] “Diarylamino” refers to R₅₅R₆₀N—, wherein R₅₅ and R₆₀ are eachindependently an aryl group, as defined herein.

[0091] “Alkylarylamino or arylalkylamino” refers to R₅₂R₅₅N—, whereinR₅₂ is an alkyl group, as defined herein, and R₅₅ is an aryl group, asdefined herein.

[0092] “Alkylarylalkylamino” refers to R₅₂R₇₉N—, wherein R₅₂ is an alkylgroup, as defined herein, and R₇₉ is an arylalkyl group, as definedherein.

[0093] “Alkylcycloalkylamino” refers to R₅₂R₈₀N—, wherein R₅₂ is analkyl group, as defined herein, and R₈₀ is an cycloalkyl group, asdefined herein.

[0094] “Aminoalkyl” refers to an amino group, an alkylamino group, adialkylamino group, an arylamino group, a diarylamino group, analkylarylamino group or a heterocyclic ring, as defined herein, to whichis appended an alkyl group, as defined herein. Exemplary aminoalkylgroups include dimethylaminopropyl, diphenylaminocyclopentyl,methylaminomethyl, and the like.

[0095] “Aminoaryl” refers to an aryl group to which is appended analkylamino group, a arylamino group or an arylalkylamino group.Exemplary aminoaryl groups include anilino, N-methylanilino,N-benzylanilino, and the like.

[0096] “Thio” refers to —S—.

[0097] “Sulfinyl” refers to —S(O)—.

[0098] “Methanthial” refers to —C(S)—.

[0099] “Thial” refers to ═S.

[0100] “Sulfonyl” refers to —S(O)₂ ⁻.

[0101] “Sulfonic acid” refers to —S(O)₂OR₇₆, wherein R₇₆ is a hydrogen,an organic cation or an inorganic cation, as defined herein.

[0102] “Alkylsulfonic acid” refers to a sulfonic acid group, as definedherein, appended to an alkyl group, as defined herein.

[0103] “Arylsulfonic acid” refers to a sulfonic acid group, as definedherein, appended to an aryl group, as defined herein

[0104] “Sulfonic ester” refers to —S(O)₂OR₅₈, wherein R₅₈ is an alkylgroup, an aryl group, or an aryl heterocyclic ring, as defined herein.

[0105] “Sulfonamido” refers to —S(O)₂—N(R₅₁)(R₅₇), wherein R₅₁ and R₅₇are each independently a hydrogen atom, an alkyl group, an aryl group oran arylheterocyclic ring, as defined herein, or R₅₁ and R₅₇ when takentogether are a heterocyclic ring, a cycloalkyl group or a bridgedcycloalkyl group, as defined herein.

[0106] “Alkylsulfonamido” refers to a sulfonamido group, as definedherein, appended to an alkyl group, as defined herein.

[0107] “Arylsulfonamido” refers to a sulfonamido group, as definedherein, appended to an aryl group, as defined herein.

[0108] “Alkylthio” refers to R₅₀S—, wherein R₅₀ is an alkyl group, asdefined herein (preferably a lower alkyl group, as defined herein).

[0109] “Arylthio” refers to R₅₅S—, wherein R₅₅ is an aryl group, asdefined herein.

[0110] “Arylalkylthio” refers to an aryl group, as defined herein,appended to an alkylthio group, as defined herein.

[0111] “Alkylsulfinyl” refers to R₅₀—S(O)—, wherein R₅₀ is an alkylgroup, as defined herein.

[0112] “Alkylsulfonyl” refers to R₅₀—S(O)₂—, wherein R₅₀ is an alkylgroup, as defined herein.

[0113] “Alkylsulfonyloxy” refers to R₅₀—S(O)₂—O—, wherein R₅₀ is analkyl group, as defined herein.

[0114] “Arylsulfinyl” refers to R₅₅—S(O)—, wherein R₅₅ is an aryl group,as defined herein.

[0115] “Arylsulfonyl” refers to R₅₅—S(O)₂—, wherein R₅₅ is an arylgroup, as defined herein.

[0116] “Arylsulfonyloxy” refers to R₅₅—S(O)₂—O—, wherein R₅₅ is an arylgroup, as defined herein.

[0117] “Amidyl” refers to R₅₁C(O)N(R₅₇)— wherein R₅₁ and R₅₇ are eachindependently a hydrogen atom, an alkyl group, an aryl group or anarylheterocyclic ring, as defined herein.

[0118] “Ester” refers to R₅₁C(O)O— wherein R₅₁ is a hydrogen atom, analkyl group, an aryl group or an arylheterocyclic ring, as definedherein.

[0119] “Carbamoyl” refers to —O—C(O)N(R₅₁)(R₅₇), wherein R₅₁ and R₅₇ areeach independently a hydrogen atom, an alkyl group, an aryl group or anarylheterocyclic ring, as defined herein, or R₅₁ and R₅₇ taken togetherare a heterocyclic ring, a cycloalkyl group or a bridged cycloalkylgroup, as defined herein.

[0120] “Carboxyl” refers to —C(O)OR₇₆, wherein R₇₆ is a hydrogen, anorganic cation or an inorganic cation, as defined herein.

[0121] “Carbonyl” refers to —C(O)—.

[0122] “Alkylcarbonyl” refers to R₅₂—C(O)—, wherein R₅₂ is an alkylgroup, as defined herein.

[0123] “Arylcarbonyl” refers to R₅₅—C(O)—, wherein R₅₅ is an aryl group,as defined herein.

[0124] “Arylalkylcarbonyl” refers to R₅₅—R₅₂—C(O)—, wherein R₅₅ is anaryl group, as defined herein, and R₅₂ is an alkyl group, as definedherein.

[0125] “Alkylarylcarbonyl” refers to R₅₂—R₅₅—C(O)—, wherein R₅₅ is anaryl group, as defined herein, and R₅₂ is an alkyl group, as definedherein.

[0126] “Heterocyclicalkylcarbonyl” refer to R₇₈C(O)— wherein R₇₈ is aheterocyclicalkyl group, as defined herein.

[0127] “Carboxylic ester” refers to —C(O)OR₅₈, wherein R₅₈ is an alkylgroup, an aryl group or an aryl heterocyclic ring, as defined herein.

[0128] “Alkylcarboxylic acid” and “alkylcarboxyl” refer to an alkylgroup, as defined herein, appended to a carboxyl group, as definedherein.

[0129] “Alkylcarboxylic ester” refers to an alkyl group, as definedherein, appended to a carboxylic ester group, as defined herein.

[0130] “Arylcarboxylic acid” refers to an aryl group, as defined herein,appended to a carboxyl group, as defined herein.

[0131] “Arylcarboxylic ester” and “arylcarboxyl” refer to an aryl group,as defined herein, appended to a carboxylic ester group, as definedherein.

[0132] “Carboxamido” refers to —C(O)N(R₅₁)(R₅₇), wherein R₅₁ and R₅₇ areeach independently a hydrogen atom, an alkyl group, an aryl group or anarylheterocyclic ring, as defined herein, or R₅₁ and R₅₇ when takentogether are a heterocyclic ring, a cycloalkyl group or a bridgedcycloalkyl group, as defined herein.

[0133] “Alkylcarboxamido” refers to an alkyl group, as defined herein,appended to a carboxarnido group, as defined herein.

[0134] “Arylcarboxarnido” refers to an aryl group, as defined herein,appended to a carboxamido group, as defined herein.

[0135] “Urea” refers to —N(R₅₉)—C(O)N(R₅₁)(R₅₇) wherein R₅₁, R₅₇, andR₅₉ are each independently a hydrogen atom, an alkyl group, an arylgroup or an arylheterocyclic ring, as defined herein, or R₅₁ and R₅₇taken together are a heterocyclic ring, a cycloalkyl group or a bridgedcycloalkyl group, as defined herein.

[0136] “Phosphoryl” refers to —P(R₇₀)(R₇₁)(R₇₂), wherein R₇₀ is a lonepair of electrons, thial or oxo, and R₇₁ and R₇₂ are each independentlya covalent bond, a hydrogen, a lower alkyl, an alkoxy, an alkylamino, ahydroxy, an oxy or an aryl, as defined herein.

[0137] Compounds that donate, transfer or release nitric oxide speciesin vivo have been recognized as having a wide spectrum of advantages andapplications. The invention is based on the unexpected discovery of theeffects of such compounds alone and together with one or more COX-2inhibitors. Treatment or prevention of inflammation, pain and fever;treatment and/or improvement of the gastrointestinal properties of COX-2inhibitors; facilitation of wound healing; and treatment and/orprevention of renal and/or respiratory toxicity and cyclooxygenase-2mediated disorders can be obtained by the use of COX-2 inhibitors of theinvention; or by the use of COX-2 inhibitors in conjunction with one ormore compounds that donate, release or transfer nitric oxide and/orstimulate endogenous production of NO and/or EDRF in vivo and/or is asubstrate for nitric oxide synthase, and, optionally, with one or moretherapeutic agents.

[0138] The COX-2 selective inhibitors, that are optionally nitrosatedand/or nitrosylated, can be used alone or in conjunction with one ormore compounds that donate, release or transfer nitric oxide and/orstimulate endogenous production of NO and/or EDRF in vivo and/or is asubstrate for nitric oxide synthase, and/or with one or more therapeuticagents, such as for example, steroids, nonsterodal anti-inflammatorycompounds (NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B₄(LTB₄) receptor antagonists, leukotriene A₄ (LTA₄) hydrolase inhibitors,3hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors, H₂antagonists, antineoplastic agents, antiplatelet agents, thrombininhibitors, thromboxane inhibitors, decongestants, diuretics, sedatingor non-sedating anti-histamines, inducible nitric oxide synthaseinhibitors, opioids, analgesics, analgesics, Helicobacter pyloriinhibitors, proton pump inhibitors, isoprostane inhibitors, and mixturesof two or more thereof. These novel compounds and novel compositions ofthe present invention are described in more detail herein.

[0139] In one embodiment, the invention described compounds of Formula(I), and pharmaceutically acceptable salts thereof;

[0140] wherein:

[0141] R₄ is methyl or ethyl;

[0142] R₅ is chloro or fluoro;

[0143] R₆ is hydrogen or fluoro;

[0144] R₇ is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy orhydroxyl;

[0145] R₈ is hydrogen or fluoro;

[0146] R₉ is chloro, fluoro, triflurormethyl or methyl;

[0147] X is an oxygen, —S(O)_(o)— or —N(R_(a))R_(i)—;

[0148] K is:

[0149] a)—W_(a)—E_(b)—(C(R_(e))(R_(f)))_(p)—E_(c)—(C(R_(e))(R_(f)))_(x)—W_(d)—(C(R_(e))(R_(f)))_(y)—W_(i)—E_(j)—W_(g)—(C(R_(e))(R_(f)))_(z)—T—Q;or

[0150] b)—W_(a)—E_(b)—(C(R_(e))(R_(f)))_(p)—E_(c)—(C(R_(e))(R_(f)))_(x)—W_(d)—(C(R_(e))(R_(f)))_(y)—W_(i)—E_(j)—W_(g)—(C(R_(e))(R_(f)))_(y)-R₃and with the proviso that at least one R_(e) is selected as —T—Q, or—(C(R_(g))(R_(h)))_(k)—T—Q when K is (b); and with the further provisothat “X—K” in the compounds of Formula (I), does not include nitroxyllower alkyl esters such as 4-(nitroxyl)butyl2(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate as disclosedin WO 99/11605;

[0151] Q is —NO or —NO₂;

[0152] a, b, c, d, g, i and j are each independently an integer from 0to 3;

[0153] p, x, y and z are each independently an integer from 0 to 10;

[0154] W at each occurrence is independently —C(O)—, —C(S)—, —T—,—(C(R_(e))(R_(f)))_(h)—, an alkyl group, an aryl group, a heterocyclicring, an arylheterocyclic ring, or —(CH₂CH₂O)_(q)—;

[0155] E at each occurrence is independently —T—, an alkyl group, anaryl group, —(C(R_(e))(R_(f)))_(h)—, a heterocyclic ring, anarylheterocyclic ring, or —(CH₂CH20)_(q)—;

[0156] h is an integer form 1 to 10;

[0157] q is an integer from 1 to 5;

[0158] R_(e) and R_(f) are each independently a hydrogen, an alkyl, acycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, anarylheterocyclic ring, an alkylaryl, an alkylcycloalkyl, analkylheterocyclic ring, a cycloalkylalkyl, a cycloalkylthio, acycloalkenyl, an heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino,an alkylamino, a dialkylamino, an arylamino, a diarylamino, analkylarylamino, an alkoxyhaloalkyl, a sulfonic acid, a sulfonic ester,an alkylsulfonic acid, an arylsulfonic acid, an arylalkoxy, analkylthio, an arylthio, a cyano an aminoalkyl, an aminoaryl, an aryl, anarylalkyl, an alkylaryl, a carboxamido, a alkylcarboxamido, anarylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylicacid, an arylcarboxylic acid, an alkylcarbonyl, an arylcarbonyl, anester, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylicester, a sulfonamido, an alkylsulfonamido, an arylsulfonamido, analkylsulfonyl, an alkylsulfonyloxy, an arylsulfonyl, arylsulphonyloxy, asulfonic ester, a urea, a phosphoryl, a nitro, W_(h), —T—Q, or—(C(R_(g))(R_(h)))_(k)—T—Q, or R_(e) and R_(f) taken together with thecarbons to which they are attached form a carbonyl, a methanthial, aheterocyclic ring, a cycloalkyl group, an aryl group, an oxime, ahydrazone or a bridged cycloalkyl group;

[0159] R_(g) and R_(h) at each occurrence are independently R_(e);

[0160] k is an integer from 1 to 3;

[0161] T at each occurrence is independently a covalent bond, acarbonyl, an oxygen, —S(O)_(o)— or —N(R_(a))R_(i)—;

[0162] o is an integer from 0 to 2;

[0163] R_(a) is a lone pair of electrons, a hydrogen or an alkyl group;

[0164] R_(i)is a hydrogen, an alkyl, an aryl, an alkylcarboxylic acid,an arylcarboxylic acid, an alkylcarboxylic ester, an arylcarboxylicester, an alkylcarboxamido, an arylcarboxamido, an alkylaryl, analkylsulfinyl, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfinyl,an arylsulfonyl, arylsulphonyloxy, a sulfonamido, a carboxamido, acarboxylic ester, an aminoalkyl, an aminoaryl,—CH₂—C(T—Q)(R_(e))(R_(f)), a bond to an adjacent atom creating a doublebond to that atom, —(N₂O₂—)⁻∘M⁺, wherein M⁺ is an organic or inorganiccation;

[0165] with the proviso that the nitrosated and/or nitrosylatedcompounds of Formula (I) must contain at least one —NO group or at leastone —NO₂ group, and wherein the at least one —NO group or the at leastone —NO₂ group is linked to the compounds of Formula (I) through anoxygen atom, a nitrogen atom or a sulfur atom.

[0166] In cases where R_(e) and R_(f) are a heterocyclic ring or R_(e)and R_(f) taken together with the carbon atoms to which they areattached are a heterocyclic ring, then R_(i) can be a substituent on anydisubstituted nitrogen contained within the radical where R_(i) is asdefined herein.

[0167] In cases where multiple designations of variables that are insequence are selected as a “covalent bond” or the integer selected is 0,the intent is to denote a single covalent bond connecting one radical toanother. For example, E₀ would denote a covalent bond, while E₂ denotes(E—E) and (C(R_(e))(R_(f)))₂ denotes —C(R_(e))(R_(f))—C(R_(e))(R_(f))—.

[0168] In a preferred embodiment of the invention, the parent COX-2selective inhibitor is2(2-((2-chloro-6-fluorophenyl)amino)₅-methylphenyl) acetic acid (COX189, registration number 220991-20-8), and its derivatives, as disclosedin, for example, WO 99/11605, WO 01/23346 and WO 02/20090, thedisclosures of each of which are incorporated by reference herein intheir entirety. The structure of the preferred embodiment parent COX-2selective inhibitor,2(2-((2chloro-6-fluorophenyl)amino)5-methylphenyl)acetic acid (COX 189),is shown below:

[0169] In other preferred embodiments of the invention, the nitrosatedderivatives of the compounds of Formula (1) are the nitrosatedderivatives of the COX-2 selective inhibitor,2(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetic acid (COX189). In even more preferred embodiments of the invention the nitrosatedderivatives of the COX-2 selective inhibitor, COX-189, are compounds ofFormula (II), (III), (IV), (V), (VI), (VII), (VIII) and (IX) andpharmaceutically acceptable salts thereof:

[0170] wherein the compound of Formula (II),2-(2-(nitroxy)ethylthio)ethyl2(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate, is:

[0171]  wherein the compound of Formula (III),2-(2-(nitroxy)ethoxy)ethyl2(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate, is:

[0172]  wherein the compound of Formula (IV), 3-((nitroxy)methylphenyl)2(2-((2-chloro-6-fluorophenyl) amino)5-methylphenyl)acetate, is:

[0173]  wherein the compound of Formula (V), 2,3-bis(nitroxy)propyl2(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate, is:

[0174]  wherein the compound of Formula (VI),6-(nitroxy)-4,8-dioxabicyclo(3.3.0)oct-2-yl2-(2((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate, is:

[0175]  wherein the compound of Formula (VII),2-((2-(nitroxy)ethyl)sulfonyl) ethyl2(2-((2chloro-6-fluorophenyl)amino)5-methylphenyl)acetate, is:

[0176]  wherein the compound of Formula (VIII),2-(4-(2-nitrooxyl)ethyl)piperazinyl)-2-oxoethyl2-(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate, is:

[0177]  wherein the compound of Formula (IX),2,3-bis(nitroxy)-4-(2-(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetyloxy)butyl2-(2-((2-chloro-6-fluorophenyl)amino)5methylphenyl)acetate,is:

[0178] Another aspect of the invention describes the metabolites of thecompounds of Formula (II), (III), (IV), (V), (VI), (VII), (VIII), (IX)and pharmaceutically acceptable salts thereof. These metabolites,include but are not limited to, the non-nitrosated derivatives of thecompounds of Formula (II), (III), (IV), (V), (VI), (VII), (VIII), (IX)and pharmaceutically acceptable salts thereof, such as, for example thecompounds of Formulas (X), (XI), (XII), (XIII), (XIV), (XV), (XVI) and(XVII):

[0179] wherein the compound of Formula (X), 2-(2-(hydroxyethylthio)ethyl2(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate, is:

[0180]  wherein the compound of Formula (XI), 2-(2-(hydroxyethoxy)ethyl2(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate, is:

[0181]  wherein the compound of Formula (XII), 3-(hydroxymethylphenyl)2(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate, is:

[0182]  wherein the compound of Formula (XIII), 2,3-dihydroxypropyl2(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate, is:

[0183]  wherein the compound of Formula (XIV),6-hydroxy-4,8-dioxabicyclo(3.3.0)oct-2-yl2(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate, is:

[0184]  wherein the compound of Formula (XV),2-((2-hydroxyethyl)sulfonyl) ethyl2(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate, is:

[0185]  wherein the compound of Formula (XVI),2-(4-(2-hydroxyethyl)piperazinyl)-2-oxoethyl2-(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate, is:

[0186]  wherein the compound of Formula (XVII),4-(2-(2-((2-chloro-6-fluorophenyl)amino)5methylphenyl)acetoxy)-2,3-dihydroxybutyl-2-(2-((2-chloro-6-fluorophenyl)amino)5methylphenyl)acetyloxy)butylacetate, is:

[0187] Compounds of the invention that have one or more asymmetriccarbon atoms may exist as the optically pure enantiomers, purediastereomers, mixtures of enantiomers, mixtures of diastereomers,racemic mixtures of enantiomers, diastereomeric racemates or mixtures ofdiastereomeric racemates. The invention includes within its scope allsuch isomers and mixtures thereof.

[0188] Another aspect of the invention provides processes for making thenovel compounds of the invention and to the intermediates useful in suchprocesses. The reactions are performed in solvents appropriate to thereagents and materials used are suitable for the transformations beingeffected. It is understood by one skilled in the art of organicsynthesis that the functionality present in the molecule must beconsistent with the chemical transformation proposed. This will, onoccasion, necessitate judgment by the routineer as to the order ofsynthetic steps, protecting groups required, and deprotectionconditions. Substituents on the starting materials may be incompatiblewith some of the reaction conditions required in some of the methodsdescribed, but alternative methods and substituents compatible with thereaction conditions will be readily apparent to one skilled in the art.The use of sulfur and oxygen protecting groups is well known forprotecting thiol and alcohol groups against undesirable reactions duringa synthetic procedure and many such protecting groups are known anddescribed by, for example, Greene and Wuts, Protective Groups in OrganicSynthesis, Third Edition, John Wiley & Sons, New York (1999).

[0189] The chemical reactions described herein are generally disclosedin terms of their broadest application for the preparation of thecompounds of this invention. The chemical reactions are described by,for example, Smith and March, March's Advanced Organic Chemistry,Reactions, Mechanisms and Structure, Fifth Edition, John Wiley & Sons,New York (2001) and by Larock, Comprehensive Organic Transformations,VCH Publishers, Inc. (1989). The compounds of the invention can besynthesized in a number of ways well known to one skilled in the art oforganic synthesis. The compounds can be synthesized using the methodsdescribed herein, together with synthetic methods known in the art ofsynthetic organic chemistry, or by convention modifications known to oneskilled in the art, e.g., by appropriate protection of interferinggroups, by changing to alternative conventional reagents, by routinemodification of reaction conditions, and the like, or other reactionsdisclosed herein or otherwise conventional, will be applicable to thepreparation of the corresponding compounds of this invention. In allpreparative methods, all starting materials are known or readilyprepared from known starting materials. Methods for the preparation ofthe compounds, include, but are not limited to, those described below.All references cited herein are hereby incorporated herein by referencein their entirety.

[0190] Nitroso compounds of Formula (I), wherein R₄, R₅, R₆, R₇, R₈, andR₉ are as defined herein, and an O-nitrosylated ester is representativeof the “X—K” group as defined herein may be prepared as described below.An appropriate acid of the compound of Formula (I) (i.e., wherein “X—K”is an hydroxyl group) is converted into the ester by reaction with anappropriate monoprotected diol. Preferred methods for the preparation ofesters are coupling the acid and the monoprotected diol by treatmentwith a dehydration agent such as dicyclohexylcarbodiimide (DCC).Alternatively, the acid may first be converted into an alkali metal saltsuch as the sodium, potassium or lithium salt, and reacted with an alkylhalide that also contains a protected hydroxyl group in a polar solventsuch as DMF to produce the ester. Preferred protecting groups for thealcohol moiety are silyl ethers such as a trimethylsilyl or atert-butyldimethylsilyl ether. Deprotection of the hydroxyl moiety(fluoride ion is the preferred method for removing silyl etherprotecting groups) followed by reaction with a suitable nitrosylatingagent such as thionyl chloride nitrite, thionyl dinitrite or nitrosiumtetrafluoroborate in a suitable anhydrous solvent such asdichlormethane, THF, DMF or acetonitrile produces the compound ofFormula (I).

[0191] Nitroso compounds of Formula (I), wherein R₄, R₅, R₆, R₇, R₈, andR₉ are as defined herein, and a S-nitrosylated ester is representativeof the “X—K” group as defined herein may be prepared as described below.An appropriate acid of the compound of Formula (I) (i.e., wherein “X—K”is a hydroxyl group) is converted into the ester by reaction with anappropriate protected thiol containing alcohol. Preferred methods forthe preparation of esters are coupling the appropriate acid andprotected thiol-containing alcohol to produce the ester by treatmentwith a dehydration agent such as DCC. Alternatively, the acid may firstbe converted into an alkali metal salt such as the sodium, potassium orlithium salt, which is then reacted with an alkyl halide which alsocontains a protected thiol group in a polar solvent such as DMF toproduce the ester. Preferred protecting groups for the thiol moiety areas a thioester such as thioacetate or thiobenzoate, as a disulfide, as athiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioethersuch as paramethoxybenzyl thioether, a tetrahydropyranyl thioether or aS-triphenylmethyl thioether. Deprotection of the thiol moiety (zinc indilute aqueous acid, triphenylphosphine in water and sodium borohydrideare preferred methods for reducing disulfide groups while aqueous baseis typically used to hydrolyze thioesters and N-methoxymethylthiocarbamates and mercuric trifluoroacetate, silver nitrate or strongacids such as trifluoroacetic or hydrochloric acid and heat are used toremove a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or aS-triphenylmethyl thioether group) followed by reaction with a suitablenitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite,a lower alkyl nitrite such as tert-butyl nitrite, or nitrosiumtetrafluoroborate in a suitable anhydrous solvent such as methylenechloride, THF, DMF or acetonitrile produces the compound of Formula (I).Alternatively, a stoichiometric quantity of sodium nitrite in an aqueousacid mixture produces the compound.of Formula (I).

[0192] The synthesis of the parent COX-2 inhibitors (i.e. non-nitrosatedand/or non-nitrosylated COX-2 inhibitors) are disclosed in, for example,WO 99/11605, WO 01/23346 and WO 02/20090, the disclosures of each ofwhich are incorporated by reference herein in their entirety. The parentCOX-2 selective inhibitor can be nitrosated and/or nitrosylated throughone or more sites such as oxygen, sulfur and/or nitrogen using themethods described in the examples herein and using conventional methodsknown to one skilled in the art. For example, known methods fornitrosating and nitrosylating compounds are described in U.S. Pat. Nos.5,380,758 and 5,703,073; 6,297,260, WO 97/27749; WO 98/19672; WO01/45703; and Oae et al, Org. Prep. Proc. Int., 15(3): 165-198 (1983),the disclosures of each of which are incorporated by reference herein intheir entirety. The methods of nitrosating and/or nitrosylating thecompounds in these references can be applied by one skilled in the artto produce any of the nitrosated and/or nitrosylated compounds ofFormula (I) described herein. The nitrosated and/or nitrosylatedcompounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII)and (IX) (i.e. nitrosated and/or nitrosylated COX-2 selectiveinhibitors) of the invention donate, transfer or release a biologicallyactive form of nitrogen monoxide (nitric oxide).

[0193] The nitrosated compounds of Formula (II), (III), (IV), (V), (VI),(VII), (VIII) or (IX) can be synthesized using the methods fornitrosating non-steroidal antinflammatory compounds (NSAIDs) disclosedin, for example, WO 94/03421, WO 94/04484, WO 94/12463, WO 95/09831, WO95/30641, WO 01/00563 and WO 01/04082, WO 01/10814 and in U.S.Application No. 60/418,353; the disclosures of each of which areincorporated by reference herein in their entirety.

[0194] The compounds of the invention include the parent COX-2inhibitors, including those described herein, which have been nitrosatedand/or nitrosylated through one or more sites such as oxygen (hydroxylcondensation), sulfur (sulfhydryl condensation) and/or nitrogen. Thenitrosated and/or nitrosylated COX-2 inhibitors of the invention donate,transfer or release a biologically active form of nitrogen monoxide(i.e., nitric oxide).

[0195] Nitrogen monoxide can exist in three forms: NO− (nitroxyl), NO•(uncharged nitric oxide) and NO+(nitrosonium). NO• is a highly reactiveshort-lived species that is potentially toxic to cells. This is criticalbecause the pharmacological efficacy of NO depends upon the form inwhich it is delivered. In contrast to the nitric oxide radical (NO•),nitrosonium (NO⁺) does not react with O₂ or O₂ ⁻ species, andfunctionalities capable of transferring and/or releasing NO⁺ and NO− arealso resistant to decomposition in the presence of many redox metals.Consequently, administration of charged NO equivalents (positive and/ornegative) is a more effective means of delivering a biologically activeNO to the desired site of action.

[0196] Compounds contemplated for use in the invention (e.g., COX-2selective inhibitor, that can be optionally nitrosated and/ornitrosylated, are, optionally, used in combination with nitric oxide andcompounds that release nitric oxide or otherwise directly or indirectlydeliver or transfer a biologically active form of nitrogen monoxide to asite of its intended activity, such as on a cell membrane in vivo.

[0197] The term “nitric oxide” encompasses uncharged nitric oxide (NO•)and charged nitrogen monoxide species, preferably charged nitrogenmonoxide species, such as nitrosonium ion (NO⁺) and nitroxyl ion (NO−) .The reactive form of nitric oxide can be provided by gaseous nitricoxide. The nitrogen monoxide releasing, delivering or transferringcompounds have the structure F-NO, wherein F is a nitrogen monoxidereleasing, delivering or transferring moiety, and include any and allsuch compounds which provide nitrogen monoxide to its intended site ofaction in a form active for its intended purpose. The term “NO adducts”encompasses any nitrogen monoxide releasing, delivering or transferringcompounds, including, for example, S-nitrosothiols, nitrites, nitrates,S-nitrothiols, sydnonimines, 2-hydroxy-2-nitrosohydrazines, (NONOates),(E)-alkyl-2-((E)- hydroxyimino)-5-nitro-3-hexeneamide (FK-409),(E)-alkyl-2((E)-hydroxyimino)-5-nitro-3-hexeneamines, N-((2Z,3E)-4-ethyl-2-(hydroxyamino)-6-methyl-5-nitro-3-heptenyl)-3-pyridinecarboxamide(FR 146801), nitrosoamines, furoxans as well as substrates for theendogenous enzymes which synthesize nitric oxide. NONOates include, butare not limited to,(Z)-1-(N-methyl-N-(6-(N-methyl-ammoniohexyl)amino))diazen-1-ium-1,2-diolate(“MAHMA/NO”),(Z)-1-(N-(3-ammoniopropyl)-N-(n-propyl)amino)diazen-1-ium-1,2-diolate(“PAPA/NO”),(Z)-1-(N-(3-aminopropyl)-N-(4-(3-aminopropylammonio)butyl)-amino)diazen-1-ium-1,2-diolate (spermine NONOate or “SPER/NO”) andsodium(Z)-1-(N,N-diethylamino)diazenium-1,2-diolate (diethylamineNONOate or “DEA/NO”) and derivatives thereof. NONOates are alsodescribed in U.S. Pat. Nos. 6,232,336, 5,910,316 and 5,650,447, thedisclosures of which are incorporated herein by reference in theirentirety. The “NO adducts” can be mono-nitrosylated, poly-nitrosylated,mono-nitrosated and/or poly-nitrosated at a variety of naturallysusceptible or artificially- provided binding sites for biologicallyactive forms of nitrogen monoxide.

[0198] One group of NO adducts is the S-nitrosothiols, which arecompounds that include at least one —S—NO group. These compounds includeS-nitroso-polypeptides (the term “polypeptide” includes proteins andpolyamino acids that do not possess an ascertained biological function,and derivatives thereof); S-nitrosylated amino acids (including naturaland synthetic amino acids and their stereoisomers and racemic mixturesand derivatives thereof); S-nitrosylated sugars; S-nitrosylated,modified and unmodified, oligonucleotides (preferably of at least 5, andmore preferably 5-200 nucleotides); straight or branched, saturated orunsaturated, aliphatic or aromatic, substituted or unsubstitutedS-nitrosylated hydrocarbons; and S-nitroso heterocyclic compounds.S-nitrosothiols and methods for preparing them are described in U.S.Pat. Nos. 5,380,758 and 5,703,073; WO 97/27749; WO 98/19672; and Oae etal, Org. Prep. Proc. Int., 15(3):165-198 (1983), the disclosures of eachof which are incorporated by reference herein in their entirety.

[0199] Another embodiment of the invention is S-nitroso amino acidswhere the nitroso group is linked to a sulfur group of asulfur-containing amino acid or derivative thereof. Such compoundsinclude, for example, S-nitroso-N-acetylcysteine, S-nitroso-captopril,S-nitroso-N-acetylpenicillamine, S-nitroso-homocysteine,S-nitroso-cysteine, S-nitroso-glutathione, S-nitroso-cysteinyl-glycine,and the like.

[0200] Suitable S-nitrosylated proteins include thiol-containingproteins (where the NO group is attached to one or more sulfur groups onan amino acid or amino acid derivative thereof) from various functionalclasses including enzymes, such as tissue-type plasminogen activator(TPA) and cathepsin B; transport proteins, such as lipoproteins; hemeproteins, such as hemoglobin and serum albumin; and biologicallyprotective proteins, such as immunoglobulins, antibodies and cytokines.Such nitrosylated proteins are described in WO 93/09806, the disclosureof which is incorporated by reference herein in its entirety. Examplesinclude polynitrosylated albumin where one or more thiol or othernucleophilic centers in the protein are modified.

[0201] Other examples of suitable S-nitrosothiols include:

[0202] (i) HS(C(R_(e))(R_(f)))_(m)SNO;

[0203] (ii) ONS(C(R_(e))(R_(f)))_(m)R_(e); or

[0204] (iii) H₂N—CH(CO₂H)—(CH₂)_(m)—C(O)NH—CH(CH₂SNO)—C(O)NH—CH₂—CO₂H;

[0205] wherein m is an integer from 2 to 20; R_(e) and R_(f) are eachindependently a hydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy,an hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring, acycloalkylalkyl, a heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino,an alkylamino, a dialkylamino, an arylamino, a diarylamino, analkylarylamino, an alkoxyhaloalkyl, a haloalkoxy, a sulfonic acid, asulfonic ester, an alkylsulfonic acid, an arylsulfonic acid, anarylalkoxy, an alkylthio, an arylthio, a cyano, an aminoalkyl, anaminoaryl, an aryl, an arylalkyl, a carboxamido, a alkylcarboxamido, anarylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylicacid, an arylcarboxylic acid, an alkylcarbonyl, an arylcarbonyl, anester, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylicester, a haloalkoxy, a sulfonamido, an alkylsulfonamido, anarylsulfonamido, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfonyl,an arylsulfonyloxy, a urea, a nitro, —T—Q—, or—(C(R_(g))(R_(h)))_(k)—T—Q or R_(e) and R_(f) taken together are an oxo,a methanthial, a heterocyclic ring, a cycloalkyl group, an oxime, ahydrazone or a bridged cycloalkyl group; Q is —NO or —NO₂; and T isindependently a covalent bond, a carbonyl, an oxygen, —S(O)_(o)— or—N(R_(a))R_(i)—, wherein o is an integer from 0 to 2, R_(a) is a lonepair of electrons, a hydrogen or an alkyl group; R_(i) is a hydrogen, analkyl, an aryl, an alkylcarboxylic acid, an arylcarboxylic acid, analkylcarboxylic ester, an arylcarboxylic ester, an alkylcarboxamido, anarylcarboxamido, an alkylsulfinyl, an alkylsulfonyl, analkylsulfonyloxy, an arylsulfinyl, an arylsulfonyloxy, an arylsulfonyl,a sulfonamido, a carboxamido, a carboxylic ester, an aminoalkyl, anaminoaryl, —CH2—C(T—Q)(R_(g))(R_(h)), or —(N₂O₂−)⁻•M⁺, wherein M⁺is anorganic or inorganic cation; with the proviso that when R_(i) is—CH₂—C(T—Q)(R_(g))(R_(h)) or —(N₂O₂—)•M⁺; then “—T—Q” can be a hydrogen,an alkyl group, an alkoxyalkyl group, an aminoalkyl group, a hydroxygroup or an aryl group; and

[0206] R_(g) and R_(h) at each occurrence are independently R_(e);

[0207] In cases where R_(e) and R_(f) are a heterocyclic ring or takentogether R_(e) and R_(f) are a heterocyclic ring, then R_(i) can be asubstituent on any disubstituted nitrogen contained within the radicalwherein R_(i) is as defined herein.

[0208] Nitrosothiols can be prepared by various methods of synthesis. Ingeneral, the thiol precursor is prepared first, then converted to theS-nitrosothiol derivative by nitrosation of the thiol group with NaNO₂under acidic conditions (pH is about 2.5) which yields the S-nitrosoderivative. Acids which can be used for this purpose include aqueoussulfuric, acetic and hydrochloric acids. The thiol precursor can also benitrosylated by reaction with an organic nitrite such as tert-butylnitrite, or a nitrosonium salt such as nitrosonium tetraflurorborate inan inert solvent.

[0209] Another group of NO adducts for use in the invention, where theNO adduct is a compound that donates, transfers or releases nitricoxide, include compounds comprising at least one ON—O— or ON—N— group.The compounds that include at least one ON—O— or ON—N— group arepreferably ON—O— or ON—N-polypeptides (the term “polypeptide” includesproteins and polyamino acids that do not possess an ascertainedbiological function, and derivatives thereof); ON—O— or ON—N-amino acids(including natural and synthetic amino acids and their stereoisomers andracemic mixtures); ON—O— or ON—N-sugars; ON—O— or —ON—N— modified orunmodified oligonucleotides (comprising at least 5 nucleotides,preferably 5-200 nucleotides); ON—O— or ON—N— straight or branched,saturated or unsaturated, aliphatic or aromatic, substituted orunsubstituted hydrocarbons; and ON—O—, ON—N— or ON—C-heterocycliccompounds.

[0210] Another group of NO adducts for use in the invention includenitrates that donate, transfer or release nitric oxide, such ascompounds comprising at least one O₂N—O—, O₂N—N— or O₂N—S— group.Preferred among these compounds are O₂N—O—, O₂N—N—or O₂N—S-polypeptides(the term “polypeptide” includes proteins and also polyamino acids thatdo not possess an ascertained biological function, and derivativesthereof); O₂N—O—, O₂N—N— or O₂N—S-amino acids (including natural andsynthetic amino acids and their stereoisomers and racemic mixtures);O₂N—O—, O₂N—N— or O₂N—S— sugars; O₂N—O—, O₂N—N— or O₂N—S— modified andunmodified oligonucleotides (comprising at least 5 nucleotides,preferably 5-200 nucleotides); O₂N—O—, O₂N—N— or O₂N—S— straight orbranched, saturated or unsaturated, aliphatic or aromatic, substitutedor unsubstituted hydrocarbons; and O₂N—O—, O₂N—N— or O₂N—S— heterocycliccompounds. Preferred examples of compounds comprising at least oneO₂N—O—, O₂N—N— or O₂N—S— group include isosorbide dinitrate, isosorbidemononitrate, clonitrate, erythrityl tetranitrate, mannitol hexanitrate,nitroglycerin, pentaerythritoltetranitrate, pentrinitrol,propatylnitrate and organic nitrates with a sulfhydryl-containing aminoacid such as, for example SPM 3672, SPM 5185, SPM 5186 and thosedisclosed in U.S. Pat. Nos. 5,284,872, 5,428,061, 5,661,129, 5,807,847and 5,883,122 and in WO 97/46521, WO 00/54756 and in WO 03/013432, thedisclosures of each of which are incorporated by reference herein intheir entirety.

[0211] Another group of NO adducts are N-oxo-N-nitrosoamines thatdonate, transfer or release nitric oxide and are represented by theformula: R^(1″)R^(2″)N—N(O—M⁺)—NO, where R^(1″) and R^(2″) are eachindependently a polypeptide, an amino acid, a sugar, a modified orunmodified oligonucleotide, a straight or branched, saturated orunsaturated, aliphatic or aromatic, substituted or unsubstitutedhydrocarbon, or a heterocyclic group, and where M⁺ is an organic orinorganic cation, such as, for example, an alkyl substituted ammoniumcation or a Group I metal cation.

[0212] The invention is also directed to compounds that stimulateendogenous NO or elevate levels of endogenous endothelium-derivedrelaxing factor (EDRF) in vivo or are substrates for nitric oxidesynthase. Such compounds include, for example, L-arginine,L-homoarginine, and N-hydroxy-L-arginine, including their nitrosated andnitrosylated analogs (e.g., nitrosated L-arginine, nitrosylatedL-arginine, nitrosated N-hydroxy-L-arginine, nitrosylatedN-hydroxy-L-arginine, nitrosated L-homoarginine and nitrosylatedL-homoarginine), precursors of L-arginine and/or physiologicallyacceptable salts thereof, including, for example, citrulline, omithine,glutamine, lysine, polypeptides comprising at least one of these aminoacids, inhibitors of the enzyme arginase (e.g., N-hydroxy-L-arginine and2(S)-amino-6-boronohexanoic acid), nitric oxide mediators and/orphysiologically acceptable salts thereof, including, for example,pyruvate, pyruvate precursors, α-keto acids having four or more carbonatoms, precursors of α-keto acids having four or more carbon atoms (asdisclosed in WO 03/017996, the disclosure of which is incorporatedherein in its entirety), and the substrates for nitric oxide synthase,cytokines, adenosin, bradykinin, calreticulin, bisacodyl, andphenolphthalein. EDRF is a vascular relaxing factor secreted by theendothelium, and has been identified as nitric oxide (NO) or a closelyrelated derivative thereof (Palmer et al, Nature, 327:524-526 (1987);Ignarro et al, Proc. Natl. Acad. Sci. USA, 84:9265-9269 (1987)).

[0213] The invention is also based on the discovery that compounds andcompositions of the invention may be used in conjunction with othertherapeutic agents for co-therapies, partially or completely, in placeof other conventional anti-inflammatory compounds, such as, for example,together with steroids, NSAIDs, 5-lipoxygenase (5-LO) inhibitors,leukotriene B₄ (LTB₄) receptor antagonists, leukotriene A₄ (LTA₄)hydrolase inhibitors, 5-HT agonists, HMG-CoA inhibitors, H₂ receptorantagonists, antineoplastic agents, antiplatelet agents, thrombininhibitors, thromboxane inhibitors, decongestants, diuretics, sedatingor non-sedating anti-histamines, inducible nitric oxide synthaseinhibitors, opiods, analgesics, Helicobacter pylori inhibitors, protonpump inhibitors, isoprostane inhibitors, and mixtures of two or morethereof.

[0214] Leukotriene A₄ (LTA₄) hydrolase inhibitors refer to compoundsthat selectively inhibit leukotriene A₄ hydrolase with an IC₅₀ of lessthan about 10 μM, and preferably with an IC₅₀ of less than about 1 μM.Suitable LTA₄ hydrolase inhibitors include, but are not limited to,RP-64966, (S,S)-3-amino4-(4-benzyloxyphenyl)-2-hydroxybutyric acidbenzyl ester,N-(2(R)-(cyclohexylmethyl)-3-(hydroxycarbamoyl)propionyl)-L-alanine,7-(4-(4-ureidobenzyl)phenyl) heptanoic acid and 3(3-(1E,3E-tetradecadienyl)-2-oxiranyl)benzoic acid lithium salt, andmixtures of two or more thereof.

[0215] Suitable LTB₄ receptor antagonists include, but are not limitedto, ebselen, linazolast, ontazolast; WAY 121006; Bay-x-1005; BI-RM-270;CGS-25019C; ETH-615; MAFP; TMK-688; T-0757; LY 213024, LY 210073, LY223982, LY 233469, LY 255283, LY 264086, LY 292728 and LY 293111;ONO-LB457, ONO-4057, and ONO-LB448, S-2474, calcitrol; PF 10042; Pfizer105696; RP 66153; SC-53228, SC-41930, SC-50605, SC-51146 and SC-53228;SB-201146 and SB-209247; SKF-104493; SM 15178; TMK-688; BPC 15, andmixtures of two or more thereof. The preferred LTB₄ receptor antagonistsare calcitrol, ebselen, Bay-x-1005, CGS-25019C, ETH-615, LY-2931 11,ONO-4057 and TMK-688, and mixtures of two or more thereof.

[0216] Suitable 5-LO inhibitors include, but are not limited to,A-76745, 78773 and ABT761; Bay-x-1005; CMI-392; E-3040; EF-40; F-1322;ML-3000; PF-5901; R-840; rilopirox, flobufen, linasolast, lonapolene,masoprocol, ontasolast, tenidap, zileuton, pranlukast, tepoxalin,rilopirox, flezelastine hydrochloride, enazadrem phosphate, andbunaprolast, and mixtures of two or more thereof. Suitable 5-LOinhibitors are also described more fully in WO 97/29776, the disclosureof which is incorporated herein by reference in its entirety.

[0217] Suitable 5-HT agonists, include, but are not limited to,rizatriptan, sumatriptan, naratriptan, zolmitroptan, eleptriptan,almotriptan, ergot alkaloids. ALX 1323, Merck L 741604 SB 220453 and LAS31416. Suitable 5-HT agonists are described more fully in WO 0025779,and in WO 00/48583. 5-HT agonists refers to a compound that is anagonist to any 5-HT receptor, including but not limited to, 5-HT₁agonists, 5-HT_(1B) agonists and 5-HT_(1D) agonists, and the like.

[0218] Suitable steroids, include, but are not limited to, budesonide,dexamethasone, corticosterone, prednisolone, and the like. Suitablesteroids are described more fully in the literature, such as in theMerck Index on CD-ROM, 13^(th) Edition.

[0219] Suitable HMG CoA inhibitors, include, but are not limited to,reductase and synthase inhibitors, such as, for example, squalenesynthetase inhibitors, benzodiazepine squalene synthase inhibitors,squalene epoxidase inhibitors, acyl-coenzyme A, bile acid sequestrants,cholesterol absorption inhibitors, and the like. Suitable HMG CoAinhibitors include simvastatin, pravastatin, lovastatin, mevastatin,fluvastatin, atorvastatin, cerivastatin, and the like, and are describedmore fully in U.S. Pat. No. 6,245,797 and WO 99/20110, the disclosuresof which are incorporated herein by reference in their entirety.

[0220] Suitable NSAIDs, include, but are not limited to, acetaminophen,aspirin, diclofenac, ibuprofen, ketoprofen, naproxen, indomethacin, andthe like. Suitable NSAIDs are described more fully in the literature,such as in Goodman and Gilman, The Pharmacological Basis of Therapeutics(9th Edition), McGraw-Hill, 1995, Pgs. 617-657; the Merck Index onCD-ROM, 13^(th) Edition; and in U.S. Pat. Nos. 6,057,347 and 6,297,260assigned to NitroMed Inc., the disclosures of which are incorporatedherein by reference in their entirety.

[0221] Suitable H₂ receptor anatgonists, include, but are not limitedto, cimetidine, roxatidine, rantidine and the like. Suitable H₂ receptorantagonists are described more fully in the literature, such as inGoodman and Gilman, The Pharmacological Basis of Therapeutics (9thEdition), McGraw-Hill, 1995, Pgs. 901-915; the Merck Index on CD-ROM,13^(th) Edition; and in WO 00/28988 assigned to NitroMed Inc., thedisclosures of which are incorporated herein by reference in theirentirety.

[0222] Suitable antineoplastic agents, include but are not limited to,5-FU-fibrinogen, acanthifolic acid, aminothiadiazole, altretamine,anaxirone, aclarubicin and the like. Suitable antineoplastic agents arealso described in U.S. Pat. No. 6,025,353 and WO 00/38730, thedisclosures of which are incorporated herein by reference in theirentirety.

[0223] Suitable antiplatelet agents, include but are not limited to,aspirin, ticlopidine, dipyridamole, clopidogrel, glycoprotein IIb/IIIareceptor antagonists, and the like. Suitable antineoplastic agents arealso described in WO 99/45913, the disclosure of which is incorporatedherein by reference in its entirety. In a preferred embodiment of theinvention, the antiplatelet agent is aspirin, more preferably, low-doseaspirin (i.e. 75 mg-100 mg/day).

[0224] Suitable thrombin inhibitors, include but are not limited to,N′-((1-(aminoiminomethyl)-4-piperidinyl)methyl)-N-(3,3-diphenylpropinyl)-L-prolineamide),3-(2-phenylethylamino)-6-methyl-1-(2-amino-6-methyl-5-methylene-carboxamidomethylpyridinyl)-2-pyrazinone,3-(2-phenethylamino)-6-methyl-1-(2-amino-6-methyl-5-methylenecarboxamidomethylpyridinyl)-2-pyridinone,and the like. Suitable thrombin inhibitors are also described in WO00/18352, the disclosure of which is incorporated herein by reference inits entirety.

[0225] Suitable thromboxane inhibitors, include but are not limited tothromboxane synthase inhibitors, thromboxane receptor antagonists, andthe like. Suitable thromboxane inhibitors, are also described in WO01/87343, the disclosure of which is incorporated herein by reference inits entirety.

[0226] Suitable decongestants include, but are not limited to,phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline,ephinephrine, naphazoline, xylometazoline, propylhexedrine,levo-desoxyephedrine, and the like.

[0227] Suitable antitussives include, but are not limited to, codeine,hydrocodone, caramiphen, carbetapentane, dextramethorphan, and the like.

[0228] Suitable proton pump inhibitors, include, but are not limited to,omeprazole, esomeprazole, lansoprazole, rabeprazole, pantoprazole, andthe like. Suitable proton pump inhibitors are described more fully inthe literature, such as in Goodman and Gilman, The Pharmacological Basisof Therapeutics (9th Edition), McGraw-Hill, 1995, Pgs. 901-915; theMerck Index on CD-ROM, 13^(th) Edition; and in WO 00/50037 assigned toNitroMed Inc., the disclosures of which are incorporated herein byreference in their entirety.

[0229] The compounds and compositions of the invention, may also be usedin combination therapies with opioids and other analgesics, including,but not limited to, narcotic analgesics, Mu receptor antagonists, Kappareceptor antagonists, non-narcotic (i.e. non-addictive) analgesics,monoamine uptake inhibitors, adenosine regulating agents, cannabinoidderivatives, neurokioin 1 receptor antagonists, Substance P antagonists,neurokinin-1 receptor antagonists, sodium channel blockers,N-methytl-D-aspartate receptor antagonists, and mixtures of two or morethereof. Preferred combination therapies would be with morphine,meperidine, codeine, pentazocine, buprenorphine, butorphanol, dezocine,meptazinol, hydrocodone, oxycodone, methadone, Tramadol ((+)enantiomer), DuP 747, Dynorphine A, Enadoline, RP-60180, HN-11608,E-2078, ICI-204448, acctominophen (paracetamol), propoxyphene,nalbuphine, E-4018, filenadol, mirtentanil, amitriptyline, DuP631,Tramadol ((-) enantiomer), GP-531, acadesine, AKI-1, AKI-2, GP-1683,GP-3269, 4030W92, tramadol racemate, Dynorphine A, E-2078, AXC3742,SNX-111, ADL2-1294, ICI-204448, CT-3, CP-99,994, CP-99,994, and mixturesof two or more thereof.

[0230] The compounds and compositions of the invention can also be usedin combination with inducible nitric oxide synthase (iNOS) inhibitors.Suitable iNOS inhibitors are disclosed in U.S. Pat. Nos. 5,132,453 and5,273,875, and in WO 97/38977 and WO 99/18960, the disclosures of eachof which are incorporated by reference herein in their entirety.

[0231] The invention is also based on the discovery that theadministraion of a therapeutically effective amount of the compounds andcompositions described herein is effective for treating inflammation,pain (both chronic and acute), and fever, such as, for example,analgesic in the treatment of pain, including, but not limited toheadache, migraines, postoperative pain, dental pain, muscular pain, andpain resulting from cancer; as an antipyretic for the treatment offever, including but not limited to, rheumatic fever, symptomsassociated with influenza or other viral infections, common cold, lowback and neck pain, dysmenorrhea, headache, toothache, sprains, strains,myositis, neuralgia, synovitis; arthritis, including but not limited torheumatoid arthritis₁ degenerative joint disease (osteoarthritis),spondyloarthropathies, gouty arthritis, systemic lupus erythematosus andjuvenile arthritis. For example, the patient can be administered atherapeutically effective amount of least one nitrosated and/ornitrosylated derivative of the COX-2 selective inhibitor of theinvention. In another embodiment, the patient can be administered atherapeutically effective amount of at least one COX-2 selectiveinhibitor, that is optionally nitrosated and /or nitrosylated, and atleast one compound that donates, transfers or releases nitric oxide, orelevates levels of endogenous EDRF or nitric oxide, or is a substratefor nitric oxide synthase. In yet another embodiment, the patient can beadministered a therapeutically effective amount of at least one COX-2selective inhibitor, that is optionally nitrosated and/or nitrosylated,and, at least one therapeutic agent, including byt not limited to,steroids, nonsterodal antiinflammatory compounds (NSAID), 5-lipoxygenase(5-LO) inhibitors, leukotriene B₄ (LTB₄) receptor antagonists,leukotriene A₄ (LTA₄) hydrolase inhibitors, 5-HT agonists,3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors, H₂antagonists, antineoplastic agents, antiplatelet agents, thrombininhibitors, thromboxane inhibitors, decongestants, diuretics, sedatingor non-sedating anti-histamines, inducible nitric oxide synthaseinhibitors, opioids, analgesics, Helicobacter pylori inhibitors, protonpump inhibitors, isoprostane inhibitors, and, optionally, at least onecompound that donates, transfers or releases nitric oxide, or elevateslevels of endogenous EDRF or nitric oxide, or is a substrate for nitricoxide synthase. The compounds can be administered separately or in theform of a composition.

[0232] Another embodiment of the invention provides methods fordecreasing and/or preventing gastrointestinal disorders and improvingthe gastrointestinal properties of the COX-2 selective inhibitor byadministering to the patient in need thereof a therapeutically effectiveamount of the compounds and/or compositions described herein, Suchgastrointestinal disorders refer to any disease or disorder of the uppergastrointestinal tract (e.g., esophagus, the stomach, the duodenum,jejunum) including, for example, inflammatory bowel disease, Crohn'sdisease, gastritis, irritable bowel syndrome, ulcerative colitis, pepticulcers, stress ulcers, gastric hyperacidity, dyspepsia, gastroparesis,Zollinger-Ellison syndrome, gastroesophageal reflux diseas, bacterialinfections (including, for example, a Helicobacter Pylori associateddisease), short-bowel (anastomosis) syndrome, hypersecretory statesassociated with systemic mastocytosis or basophilic leukemia andhyperhistaminemia, and bleeding peptic ulcers that result, for example,from neurosurgery, head injury, severe body trauma or burns. Forexample, the patient can be administered a therapeutically effectiveamount of at least one nitrosated and/or nitrosylated derivative of theCOX-2 selective inhibitor of the invention. In another embodiment, thepatient can be administered a therapeutically effective amount of atleast one COX-2 selective inhibitor, that is optionally nitrosatedand/or nitrosylated, and at least one compound that donates, transfersor releases nitric oxide, or elevates levels of endogenous EDRF ornitric oxide, or is a substrate for nitric oxide synthase. In yetanother embodiment, the patient can be administered a therapeuticallyeffective amount of at least one COX-2 selective inhibitor, that isoptionally nitrosated and/or nitrosylated, and, at least one therapeuticagent, including but not limited to, including but not limited to,steroids, nonsterodal anti-inflammatory compounds (NSAID),5-lipoxygenase (5-LO) inhibitors, leukotriene B₄ (LTB₄) receptorantagonists, leukotriene A₄ (LTA₄) hydrolase inhibitors, 5-HT agonists,3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors, H₂antagonists, antineoplastic agents, antiplatelet agents, thrombininhibitors, thromboxane inhibitors, decongestants, diuretics, sedatingor non-sedating anti-histamines, inducible nitric oxide synthaseinhibitors, opioids, analgesics, Helicobacter pylori inhibitors, protonpump inhibitors, isoprostane inhibitors, and, optionally, at least onecompound that donates, transfers or releases nitric oxide, or elevateslevels of endogenous EDRF or nitric oxide, or is a substrate for nitricoxide synthase. The compounds can be administered separately or in theform of a composition.

[0233] Yet another embodiment of the invention provides methods forfacilitating wound healing (such as, for example, ulcer healing, bonehealing including osteoporosis) by administering to the patient in needthereof a therapeutically effective amount of the compounds and/orcompositions described herein. Wound refers to, and includes, any lesionthat is characterized by loss of tissue, and, includes, but are notlimited to, ulcers, cuts, burns, bone fractures, orthopedic procedure,would infliction, and the like. Ulcers refers to lesions of the uppergastrointestinal tract lining that are characterized by loss of tissue,and, include, but are not limited to, gastric ulcers, duodenal ulcers,gastritis, and the like. For example, the patient can be administered atherapeutically effective amount of at least one nitrosated and/ornitrosylated derivative of the COX-2 selective inhibitor of theinvention. In another embodiment, the patient can be administered atherapeutically effective amount of at least one COX-2 selectiveinhibitor, that is optionally nitrosated and/or nitrosylated, and atleast one compound that donates, transfers or releases nitric oxide, orelevates levels of endogenous EDRF or nitric oxide, or is a substratefor nitric oxide synthase. In yet another embodiment, the patient can beadministered a therapeutically effective amount of at least one COX-2selective inhibitor, that is optionally nitrosated and/or nitrosylated,and, at least one therapeutic agent, and, optionally, at least onenitric oxide donor. The compounds can be administered separately or inthe form of a composition.

[0234] Another embodiment of the invention provides methods to decreaseor reverse renal and other toxicities (such as, for example, kidneytoxicity, respiratory toxicity) by administering to a patient in needthereof a therapeutically effective amount of the compounds and/orcompositions described herein. For example, the patient can beadministered a therapeutically effective amount of at least onenitrosated and/or nitrosylated COX-2 selective inhibitor of theinvention. In another embodiment, the patient can be administered atherapeutically effective amount of at least one COX-2 selectiveinhibitor, that is optionally nitrosated and/or nitrosylated, and atleast one nitric oxide donor. In yet another embodiment, the patient canbe administered a therapeutically effective amount of at least one COX-2selective inhibitor, that is optionally nitrosated and/or nitrosylated,and at least one therapeutic agent, and, optionally, at least one nitricoxide donor. The compounds can be administered separately or in the formof a composition.

[0235] Another embodiment of the invention provides methods to treat orprevent disorders resulting from elevated levels of COX-2 byadministering to a patient in need thereof a therapeutically effectiveamount of the compounds and/or compositions described herein. Forexample, the patient can be administered a therapeutically effectiveamount of at least one COX2 selective inhibitor, that is optionallynitrosated and/or nitrosylated, of the invention. In another embodiment,the patient can be administered a therapeutically effective amount of atleast one COX-2 selective inhibitor, that is optionally nitrosatedand/or nitrosylated, and at least one compound that donates, transfersor releases nitric oxide, or elevates levels of endogenous EDRF ornitric oxide, or is a substrate for nitric oxide synthase. In yetanother embodiment, the patient can be administered a therapeuticallyeffective amount of at least one COX-2 selective inhibitor, that isoptionally nitrosated and/or nitrosylated, and at least one therapeuticagent, including but not limited to, steroids, a nonsterodalanti-inflammatory compounds (NSAID), 5-lipoxygenase (5-LO) inhibitors,leukotriene B₄ (LTB₄) receptor antagonists, leukotriene A₄ (LTA₄)hydrolase inhibitors, 5-HT agonists, 3-hydroxy-3-methylglutaryl coenzymeA (HMG-CoA) inhibitors, H₂ antagonists, antineoplastic agents,antiplatelet agents, thrombin inhibitors, thromboxane inhibitors,decongestants, diuretics, sedating or non-sedating anti-histamines,inducible nitric oxide synthase inhibitors, opioids, analgesics,Helicobacter pylori inhibitors, proton pump inhibitors, isoprostaneinhibitors, and, optionally, at least one compound that donates,transfers or releases nitric oxide, or elevates levels of endogenousEDRF or nitric oxide, or is a substrate for nitric oxide synthase. Thecompounds can be administered separately or in the form of acomposition.

[0236] Disorders resulting from elevated levels of COX-2 (e.g., COX-2mediated disorders) include, but are not limited to, for example,angiogenisis, arthritis, asthma, bronchitis, menstrual cramps, prematurelabor, tendinitis, bursitis; skin-related conditions, such as, forexample, psoriasis, eczema, surface wounds, burns and dermatitis;post-operative inflammation including from ophthalmic surgery, such as,for example, cataract surgery and refractive surgery, and the like;treatment of neoplasia, such as, for example, brain cancer, bone cancer,epithelial cell-derived neoplasia (epithelial carcinoma), such as, forexample, basal cell carcinoma, adenocarcinoma, gastrointestinal cancer,such as, for example, lip cancer, mouth cancer, esophageal cancer, smallbowel cancer and stomach cancer, colon cancer, liver cancer, bladdercancer, pancreas cancer, ovary cancer, cervical cancer, lung cancer,breast cancer and skin cancer, such as squamus cell and basal cellcancers, prostate cancer, renal cell carcinoma, and other known cancersthat effect epithelial cells throughout the body, benign and canceroustumors, growths, polyps, adenomatous polyps, including, but not limitedto, familial adenomatous polyposis, fibrosis resulting from radiationtherapy, and the like; treatment of inflammatory processes in diseases,such as, for example, vascular diseases, migraine headaches,periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease,sclerodoma, rheumatic fever, type I diabetes, neuromuscular junctiondisease including myasthenia gravis, white matter disease includingmultiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome,polymyositis, gingivitis, nephritis, hypersensitivity, swellingoccurring after injury, myocardial ischemia, and the like; treatment ofophthalmic diseases and disorders, such as, for example, retinitis,retinopathies, uveitis, ocular photophobia, acute injury to the eyetissue, glaucoma, inflammation of the eye and elevation of intraocularpressure and the like; treatment of pulmonary inflammation, such as, forexample, those associated with viral infections and cystic fibrosis, andthe like; treatment of central nervous system disorders, such as, forexample, cortical dementias including Alzheimer's disease, vasculardementia, multi-infarct dementia, presenile dementia, alcoholicdementia, senile dementia, and central nervous system damage resultingfrom stroke, ischemia and trauma, and the like; treatment of allergicrhinitis, respiratory distress syndrome, endotoxin shock syndrome,atherosclerosis; treatment of inflammations and/or microbial infectionsincluding, for example, inflammations and/or infections of the eyes,ears, nose, throat, and/or skin; treatment and/or prevention ofcardiovascular disorders, such as, for example, coronary artery disease,aneurysm, arteriosclerosis, atherosclerosis, including, but not limitedto, cardiac transplant atherosclerosis, myocardial infaraction,hypertension, ischemia, embolism, stroke, thrombosis, venous thrombosis,thromboembolism, thrombotic occlusion and reclusion, restenosis, angina,unstable angina, shock, heart failure, coronary plaque inflammation,bacterial-induced inflammation, such as, for example, Chlamydia-inducedinflammation, viral induced inflammation, inflammation associated withsurgical procedures, such as, for example, vascular grafting, coronaryartery bypass surgery, revascularization procedures, such as, forexample, angioplasty, stent placement, endarterectomy, vascularprocedures involving arteries, veins, capillaries, and the like;treatment and/or prevention of urinary and/or urological disorders, suchas, for example, incontinence and the like; treatment and/or preventionof endothelial dysfunctions, such as, for example, diseases accompanyingthese dysfunctions, endothelial damage from hypercholesterolemia,endothelial damage from hypoxia, endothelial damage from mechanical andchemical noxae, especially during and after drug, and mechanicalreopening of stenosed vessels, for example, following percutaneoustransluminal angiography (PTA) and percuntaneous transluminal coronaryangiography (PTCA), endothelial damage in postinfarction phase,endothelium-mediated reocculusion following bypass surgery, blood supplydistrubances in peripheral arteries, as well as, cardiovasculardiseases, and the like; disorders treated by the preservation of organsand tissues, such as, for example, for organ transplants, and the like;disorders treated by the inhibition and/or prevention of activation,adhesion and infiltration of neutrophils at the site of inflammation;and disorders treated by the inhibition and/or prevention of plateletaggregation. The compounds and compositions of the invention can also beused as a pre-anesthetic medication in emergency operations to reducethe danger of aspiration of acidic gastric contents.

[0237] Another embodiment of the invention provides methods forimproving the cardiovascular profile of COX-2 selective inhibitors byadministering to a patient in need thereof a therapeutically effectiveamount of the compounds and/or compositions described herein. Forexample, the patient can be administered a therapeutically effectiveamount of at least one nitrosated and/or nitrosylated COX-2 selectiveinhibitor of the invention. In another embodiment, the patient can beadministered a therapeutically effective amount of at least one COX-2selective inhibitor, that is optionally nitrosated and/or nitrosylated,and at least one nitric oxide donor. In yet another embodiment, thepatient can be administered a therapeutically effective amount of atleast one COX-2 selective inhibitor, that is optionally nitrosatedand/or nitrosylated, at least one of 3-hydroxy-3-methylglutaryl coenzymeA (HMG-CoA) inhibitors, antiplatelet agents, thrombin inhibitors,thromboxane inhibitors, and, optionally, at least one nitric oxidedonor. The compounds can be administered separately or in the form of acomposition.

[0238] When administered separately, the COX-2 selective inhibitor, thatis optionally nitrosated and/or nitrosylated, can be administered aboutthe same time as part of the overall treatment regimen i.e., as acombination therapy. “About the same time” includes administering theCOX2 selective inhibitor, that is optionally nitrosated and/ornitrosylated, simultaneously, sequentially, at the same time, atdifferent times on the same day, or on different days, as long as theyare administered as part of an overall treatment regimen, i.e.,combination therapy or a therapeutic cocktail.

[0239] When administered in vivo, the compounds and compositions of theinvention can be administered in combination with pharmaceuticallyacceptable carriers and in dosages described herein. When the compoundsand compositions of the invention are administered as a combination ofat least one COX-2 selective inhibitor and/or at least one nitrosatedand/or nitrosylated COX-2 selective inhibitor and/or at least one nitricoxide donor and/or therapeutic agent, they can also be used incombination with one or more additional compounds which are known to beeffective against the specific disease state targeted for treatment. Thenitric oxide donors, therapeutic agents and/or other additionalcompounds can be administered simultaneously with, subsequently to, orprior to administration of the COX-2 selective inhibitor and/ornitrosated and/or nitrosylated COX-2 selective inhibitor.

[0240] The compounds and compositions of the invention can beadministered by any available and effective delivery system including,but not limited to, orally, bucally, parenterally, by inhalation spray,by topical application, by injection, transdermally, or rectally (e.g.,by the use of suppositories) in dosage unit formulations containingconventional nontoxic pharmaceutically acceptable carriers, adjuvants,and vehicles, as desired. Parenteral includes subcutaneous injections,intravenous, intramuscular, intrasternal injection, or infusiontechniques.

[0241] Transdermal compound administration, which is known to oneskilled in the art, involves the delivery of pharmaceutical compoundsvia percutaneous passage of the compound into the systemic circulationof the patient. Topical administration can also involve the use oftransdermal administration such as transdermal patches or iontophoresisdevices. Other components can be incorporated into the transdermalpatches as well. For example, compositions and/or transdermal patchescan be formulated with one or more preservatives or bacteriostaticagents including, but not limited to, methyl hydroxybenzoate, propylhydroxybenzoate, chlorocresol, benzalkonium chloride, and the like.Dosage forms for topical administration of the compounds andcompositions can include creams, sprays, lotions, gels, ointments, eyedrops, nose drops, ear drops, and the like. In such dosage forms, thecompositions of the invention can be mixed to form white, smooth,homogeneous, opaque cream or lotion with, for example, benzyl alcohol 1%or 2% (wt/wt) as a preservative, emulsifying wax, glycerin, isopropylpalmitate, lactic acid, purified water and sorbitol solution. Inaddition, the compositions can contain polyethylene glycol 400. They canbe mixed to form ointments with, for example, benzyl alcohol 2% (wt/wt)as preservative, white petrolatum, emulsifying wax, and tenox II(butylated hydroxyanisole, propyl gallate, citric acid, propyleneglycol). Woven pads or rolls of bandaging material, e.g., gauze, can beimpregnated with the compositions in solution, lotion, cream, ointmentor other such form can also be used for topical application. Thecompositions can also be applied topically using a transdermal system,such as one of an acrylic-based polymer adhesive with a resinouscrosslinking agent impregnated with the composition and laminated to animpermeable backing.

[0242] Solid dosage forms for oral administration can include capsules,tablets, effervescent tablets, chewable tablets, pills, powders,sachets, granules and gels. In such solid dosage forms, the activecompounds can be admixed with at least one inert diluent such assucrose, lactose or starch. Such dosage forms can also comprise, as innormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, effervescent tablets, and pills, the dosage forms can alsocomprise buffering agents. Soft gelatin capsules can be prepared tocontain a mixture of the active compounds or compositions of theinvention and vegetable oil. Hard gelatin capsules can contain granulesof the active compound in combination with a solid, pulverulent carriersuch as lactose, saccharose, sorbitol, mannitol, potato starch, cornstarch, amylopectin, cellulose derivatives of gelatin. Tablets and pillscan be prepared with enteric coatings.

[0243] Liquid dosage forms for oral administration can includepharmaceutically acceptable emulsions, solutions, suspensions, syrups,and elixirs containing inert diluents commonly used in the art, such aswater. Such compositions can also comprise adjuvants, such as wettingagents, emulsifying and suspending agents, and sweetening, flavoring,and perfuming agents.

[0244] Suppositories for vaginal or rectal administration of thecompounds and compositions of the invention, such as for treatingpediatric fever and the like, can be prepared by mixing the compounds orcompositions with a suitable nonirritating excipient such as cocoabutter and polyethylene glycols which are solid at room temperature butliquid at rectal temperature, such that they will melt in the rectum andrelease the drug.

[0245] Injectable preparations, for example, sterile injectable aqueousor oleaginous suspensions can be formulated according to the known artusing suitable dispersing agents, wetting agents and/or suspendingagents. The sterile injectable preparation can also be a sterileinjectable solution or suspension in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that can be used are water,Ringer's solution, and isotonic sodium chloride solution. Sterile fixedoils are also conventionally used as a solvent or suspending medium.

[0246] The compositions of this invention can further includeconventional excipients, i.e., pharmaceutically acceptable organic orinorganic carrier substances suitable for parenteral application whichdo not deleteriously react with the active compounds. Suitablepharmaceutically acceptable carriers include, for example, water, saltsolutions, alcohol, vegetable oils, polyethylene glycols, gelatin,lactose, amylose, magnesium stearate, talc, surfactants, silicic acid,viscous paraffin, perfume oil, fatty acid monoglycerides anddiglycerides, petroethral fatty acid esters, hydroxymethyl-cellulose,polyvinylpyrrolidone, and the like. The pharmaceutical preparations canbe sterilized and if desired, mixed with auxiliary agents, e.g.,lubricants, preservatives, stabilizers, wetting agents, emulsifiers,salts for influencing osmotic pressure, buffers, colorings, flavoringand/or aromatic substances and the like which do not deleteriously reactwith the active compounds. For parenteral application, particularlysuitable vehicles consist of solutions, preferably oily or aqueoussolutions, as well as suspensions, emulsions, or implants. Aqueoussuspensions may contain substances which increase the viscosity of thesuspension and include, for example, sodium carboxymethyl cellulose,sorbitol and/or dextran. Optionally, the suspension may also containstabilizers.

[0247] The composition, if desired, can also contain minor amounts ofwetting agents, emulsifying agents and/or pH buffering agents. Thecomposition can be a liquid solution, suspension, emulsion, tablet,pill, capsule, sustained release formulation, or powder. The compositioncan be formulated as a suppository, with traditional binders andcarriers such as triglycerides. Oral formulations can include standardcarriers such as pharmaceutical grades of mannitol, lactose, starch,magnesium stearate, sodium saccharine, cellulose, magnesium carbonate,and the like.

[0248] Various delivery systems are known and can be used to administerthe compounds or compositions of the invention, including, for example,encapsulation in liposomes, microbubbles, emulsions, microparticles,microcapsules and the like. The required dosage can be administered as asingle unit or in a sustained release form.

[0249] The bioavailabilty of the compositions can be enhanced bymicronization of the formulations using conventional techniques such asgrinding, milling, spray drying and the like in the presence of suitableexcipients or agents such as phospholipids or surfactants.

[0250] The preferred methods of administration of the COX-2 selectiveinhibitors and compositions for the treatment of gastrointestinaldisorders are orally, bucally or by inhalation. The preferred methods ofadministration for the treatment of inflammation and microbialinfections are orally, bucally, topically, transdermally or byinhalation.

[0251] The compounds and compositions of the invention can be formulatedas pharmaceutically acceptable salt forms. Pharmaceutically acceptablesalts include, for example, alkali metal salts and addition salts offree acids or free bases. The nature of the salt is not critical,provided that it is pharmaceutically-acceptable. Suitablepharmaceutically-acceptable acid addition salts may be prepared from aninorganic acid or from an organic acid. Examples of such inorganic acidsinclude, but are not limited to, hydrochloric, hydrobromic, hydroiodic,nitric, carbonic, sulfuric and phosphoric acid and the like. Appropriateorganic acids include, but are not limited to, aliphatic,cycloaliphatic, aromatic, heterocyclic, carboxylic and sulfonic classesof organic acids, such as, for example, formic, acetic, propionic,succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic,glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic,mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic,benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesuifonic,sulfanilic, stearic, algenic, β-hydroxybutyric, cyclohexylaminosulfonic,galactaric and galacturonic acid and the like. Suitablepharmaceutically-acceptable base addition salts include, but are notlimited to, metallic salts made from aluminum, calcium, lithium,magnesium, potassium, sodium and zinc or organic salts made fromprimary, secondary and tertiary amines, cyclic amines,N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine) and procaine and thelike. All of these salts may be prepared by conventional means from thecorresponding compound by reacting, for example, the appropriate acid orbase with the compound.

[0252] While individual needs may vary, determination of optimal rangesfor effective amounts of the compounds and/or compositions is within theskill of the art. Generally, the dosage required to provide an effectiveamount of the compounds and compositions, which can be adjusted by oneof ordinary skill in the art, will vary depending on the age, health,physical condition, sex, diet, weight, extent of the dysfunction of therecipient, frequency of treatment and the nature and scope of thedysfunction or disease, medical condition of the patient, the route ofadministration, pharmacological considerations such as the activity,efficacy, pharmacokinetic and toxicology profiles of the particularcompound used, whether a drug delivery system is used, and whether thecompound is administered as part of a drug combination.

[0253] The amount of a given COX-2 selective inhibitor of the inventionthat will be effective in the treatment of a particular disorder orcondition will depend on the nature of the disorder or condition, andcan be determined by standard clinical techniques, including referenceto Goodman and Gilman, supra; The Physician's Desk Reference, MedicalEconomics Company, Inc., Oradell, N.J., 1995; and Drug Facts andComparisons, Inc., St. Louis, Mo., 1993. The precise dose to be used inthe formulation will also depend on the route of administration, and theseriousness of the disease or disorder, and should be decided by thephysician and the patient's circumstances.

[0254] The amount of nitric oxide donor in a pharmaceutical compositioncan be in amounts of about 0.1 to about 10 times the molar equivalent ofthe COX-2 selective inhibitor. The usual daily doses of the COX-2selective inhibitors are about 0.001 mg to about 140 mg/kg of bodyweight per day, preferably 0.005 mg to 30 mg/kg per day, oralternatively about 0.5 mg to about 7 g per patient per day. Forexample, inflammations may be effectively treated by the administrationof from about 0.01 mg to 50 mg of the compound per kilogram of bodyweight per day, or alternatively about 0.5 mg to about 3.5 g per patientper day. The compounds may be administered on a regimen of up to 6 timesper day, preferably 1 to 4 times per day, and most preferably once perday. Effective doses may be extrapolated from dose-response curvesderived from in vitro or animal model test systems and are in the sameranges or less than as described for the commercially availablecompounds in the Physician's Desk Reference, supra.

[0255] The invention also provides pharmaceutical kits comprising one ormore containers filled with one or more of the ingredients of thepharmaceutical compounds and/or compositions of the invention,including, at least, one or more of the novel COX-2 selectiveinhibitors, that is optionally nitrosated and/or nitrosylated, and oneor more of the NO donors described herein. Associated with such kits canbe additional therapeutic agents or compositions (e.g., steroids,NSAIDs, 5-lipoxygenase (5-LO) inhibitors, leukotriene B₄ (LTB₄) receptorantagonists and leukotriene A₄ (LTA₄) hydrolase inhibitors, 5-HTagonists, HMG-CoA inhibitors, H₂ antagonists, antineoplastic agents,antiplatelet agents, thrombin inhibitors, thromboxane inhibitors,decongestants, diuretics, sedating or non-sedating anti-histamines,inducible nitric oxide synthase inhibitors, opioids, analgesics,Helicobacter pylori inhibitors, proton pump inhibitors, isoprostaneinhibitors, and the like), devices for administering the compositions,and notices in the form prescribed by a governmental agency regulatingthe manufacture, use or sale of pharmaceuticals or biological productswhich reflects approval by the agency of manufacture, use or sale forhumans.

What is claimed is:
 1. A compound of Formula (I) or a pharmaceuticallyacceptable salt thereof, wherein the compound of Formula (I) is:

wherein: R₄ is methyl or ethyl; R₅ is chloro or fluoro; R₆ is hydrogenor fluoro; R₇ is hydrogen, fluoro, chloro, methyl, ethyl, methoxy,ethoxy or hydroxyl; R₈ is hydrogen or fluoro; R₉ is chloro, fluoro,triflurormethyl or methyl; X is an oxygen, —S(O)_(o)— or—N(R_(a))R_(i)—; K is: a)—W_(a)—E_(b)—(C(R_(e))(R_(f)))_(p)—E_(c)—(C(R_(e))(R_(f)))_(x)—W_(d)—(C(R_(e))(R_(f)))_(y)—W_(i)—E_(j)—W_(g)—(C(R_(e))(R_(f)))₂—T—Q;or b)—W_(a)—E_(b)—(C(R_(e))(R_(f)))_(p)—E_(c)—(C(R_(e))(R_(f)))_(x)—W_(d)—(C(R_(e))(R_(f)))_(y)—W_(i)—E_(j)—W_(g)—(C(R_(e))(R_(f)))_(z)—R₃and with the proviso that at least one R_(e) is selected as —T—Q, or—(C(R_(g))(R_(h)))_(k)—T—Q when K is (b); and with the further provisothat “X—K” in the compounds of Formula (I), does not include nitroxyllower alkyl esters; R₃ is:

Q is —NO or —NO₂; a, b, c, d, g, i and j are each independently aninteger from 0 to 3; p, x, y and z are each independently an integerfrom 0 to 10; W at each occurrence is independently —C(O)—, —C(S)—, —T—,—(C(R_(e))(R_(f)))_(h)—, an alkyl group, an aryl group, a heterocyclicring, an arylheterocyclic ring, or —(CH₂CH₂O)_(q)—; E at each occurrenceis independently —T—, an alkyl group, an aryl group,—(C(R_(e))(R_(f)))_(h)—, a heterocyclic ring, an arylheterocyclic ring,or —(CH₂CH₂O)_(q)—; h is an integer form 1 to 10; q is an integer from 1to 5; R_(e) and R_(f) are each independently a hydrogen, an alkyl, acycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, anarylheterocyclic ring, an alkylaryl, an alkylcycloalkyl, analkylheterocyclic ring, a cycloalkylalkyl, a cycloalkylthio, acycloalkenyl, an heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino,an alkylamino, a dialkylamino, an arylamino, a diarylamino, analkylarylamino, an alkoxyhaloalkyl, a sulfonic acid, a sulfonic ester,an alkylsulfonic acid, an arylsulfonic acid, an arylalkoxy, analkylthio, an arylthio, a cyano an aminoalkyl, an aminoaryl, an aryl, anarylalkyl, an alkylaryl, a carboxamido, a alkylcarboxamido, anarylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylicacid, an arylcarboxylic acid, an alkylcarbonyl, an arylcarbonyl, anester, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylicester, a sulfonamido, an alkylsulfonamido, an arylsulfonamido, analkylsulfonyl, an alkylsulfonyloxy, an arylsulfonyl, arylsulphonyloxy, asulfonic ester, a urea, a phosphoryl, a nitro, W_(h), —T—Q, or—(C(R_(g))(R_(h)))_(k)—T—Q, or R_(e) and R_(f) taken together with thecarbons to which they are attached form a carbonyl, a methanthial, aheterocyclic ring, a cycloalkyl group, an aryl group, an oxime, ahydrazone or a bridged cycloalkyl group; R_(g) and R_(h) at eachoccurrence are independently R_(e); k is an integer from 1 to 3; T ateach occurrence is independently a covalent bond, a carbonyl, an oxygen,—S(O)_(o)— or —N(R_(a))R_(i)—; o is an integer from 0 to 2; R_(a) is alone pair of electrons, a hydrogen or an alkyl group; R_(i) is ahydrogen, an alkyl, an aryl, an alkylcarboxylic acid, an arylcarboxylicacid, an alkylcarboxylic ester, an arylcarboxylic ester, analkylcarboxamido, an arylcarboxarnido, an alkylaryl, an alkylsulfinyl,an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfinyl, an arylsulfonyl,arylsulphonyloxy, a sulfonamido, a carboxamido, a carboxylic ester, anaminoalkyl, an aminoaryl, —CH₂—C(T—Q)(R_(e))(R_(f)), a bond to anadjacent atom creating a double bond to that atom, —(N₂O₂—)⁻•M⁺, whereinM⁺ is an organic or inorganic cation; with the proviso that thenitrosated and/or nitrosylated compounds of Formula (I) must contain atleast one —NO group or at least one —NO₂ group, and wherein the at leastone —NO group or the at least one —NO₂ group is linked to the compoundsof Formula (I) through an oxygen atom, a nitrogen atom or a sulfur atom.2. A composition comprising the compound of claim 1 and apharmaceutically acceptable carrier.
 3. A method for treating orreducing inflammation, pain or fever in a patient in need thereofcomprising administering to the patient a therapeutically effectiveamount of the composition of claim
 2. 4. A method for treating agastrointestinal disorder, or improving the gastrointestinal propertiesof a COX-2 inhibitor in a patient in need thereof comprisingadministering to the patient a therapeutically effective amount of thecomposition of claim
 2. 5. The method of claim 4, wherein thegastrointestinal disorder is an inflammatory bowel disease, Crohn'sdisease, gastritis, irritable bowel syndrome, ulcerative colitis, apeptic ulcer, a stress ulcer, a bleeding ulcer, gastric hyperacidity,dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophagealreflux disease, a bacterial infection, short-bowel (anastomosis)syndrome, or a hypersecretory state associated with systemicmastocytosis or basophilic leukemia and hyperhistaminemia.
 6. A methodfor facilitating wound healing in a patient in need thereof comprisingadministering to the patient a therapeutically effective amount of thecomposition of claim
 2. 7. The method of claim 6, wherein the wound isan ulcer.
 8. A method for treating or reversing renal and/or respiratorytoxicity in a patient in need thereof comprising administering to thepatient a therapeutically effective amount of the composition of claim2.
 9. A method for treating a disorder resulting from elevated levels ofCOX-2 in a patient in need thereof comprising administering to thepatient a therapeutically effective amount of the composition of claim2.
 10. The method of claim 9, wherein the disorder resulting fromelevated levels of COX-2 is angiogenesis, arthritis, asthma, bronchitis,menstrual cramps, premature labor, tendinitis, bursitis, skin-relatedcondition, neoplasia, inflammatory processes in diseases, ophthalmicdisorder, pulmonary inflammation, central nervous system disorder,allergic rhinitis, respiratory distress syndrome, endotoxin shocksyndrome, atherosclerosis, inflammation and/or microbial infection,cardiovascular disorder, urinary and/or urological disorder, endothelialdysfunction, preservation of organs and tissues, inhibition ofactivation, adhesion and infiltration of neutrophils at the site ofinflammation, or inhibition of platelet aggregation.
 11. The method ofclaim 10, wherein the neoplasia is a brain cancer, a bone cancer, anepithelial cell-derived neoplasia (epithelial carcinoma), a basal cellcarcinoma, an adenocarcinoma, a gastrointestinal cancer, a lip cancer, amouth cancer, an esophageal cancer, a small bowel cancer, a stomachcancer, a colon cancer, a liver cancer, a bladder cancer, a pancreascancer, an ovary cancer, a cervical cancer, a lung cancer, a breastcancer, a skin cancer, a squamus cell cancer, a basal cell cancer, aprostate cancer, a renal cell carcinoma, a cancerous tumor, a growth, apolyp, an adenomatous polyp, a familial adenomatous polyposis or afibrosis resulting from radiation therapy.
 12. The method of claim 10,wherein the central nervous system disorder is cortical dementias,Alzheimer's disease, vascular dementia, multi-infarct dementia,pre-senile dementia, alcoholic dementia, senile dementia, centralnervous system damage resulting from stroke, ischemia or trauma.
 13. Amethod for inhibiting platelet aggregation in a patient in need thereofcomprising administering to the patient a therapeutically effectiveamount of the composition of claim
 2. 14. The composition of claim 2,further comprising at least one therapeutic agent.
 15. The compositionof claim 14, wherein the therapeutic agent is a steroid, a nonsteroidalanti-inflammatory compound, a 5-lipoxygenase (5-LO) inhibitor, aleukotriene B₄ receptor antagonist, a leukotriene A₄ hydrolaseinhibitor, a 5-HT agonist, a HMG CoA inhibitor, a H₂ antagonist, anantineoplastic agent, an antiplatelet agent, a thrombin inhibitor, athromboxane inhibitor, a decongestant, a diuretic, a sedating ornon-sedating anti-histamine, an inducible nitric oxide synthaseinhibitor, an opioid, an analgesic, a Helicobacter pylori inhibitor, aproton pump inhibitor, an isoprostane inhibitor, or a mixture of two ormore thereof.
 16. A method for treating or reducing inflammation, painor fever in a patient in need thereof comprising administering to thepatient a therapeutically effective amount of the composition of claim14.
 17. A method for treating a gastrointestinal disorder, or improvingthe gastrointestinal properties of a COX-2 inhibitor in a patient inneed thereof comprising administering to the patient a therapeuticallyeffective amount of the composition of claim
 14. 18. The method of claim17, wherein the gastrointestinal disorder is an inflammatory boweldisease, Crohn's disease, gastritis, irritable bowel syndrome,ulcerative colitis, a peptic ulcer, a stress ulcer, a bleeding ulcer,gastric hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellisonsyndrome, gastroesophageal reflux disease, a bacterial infection,short-bowel (anastomosis) syndrome, or a hypersecretory state associatedwith systemic mastocytosis or basophilic leukemia and hyperhistaminemia.19. A method for facilitating wound healing in a patient in need thereofcomprising administering to the patient a therapeutically effectiveamount of the composition of claim
 84. 20. The method of claim 19,wherein the wound is an ulcer.
 21. A method for treating or reversingrenal and/or respiratory toxicity in a patient in need thereofcomprising administering to the patient a therapeutically effectiveamount of the composition of claim
 14. 22. A method for treating adisorder resulting from elevated levels of COX-2 in a patient in needthereof comprising administering to the patient a therapeuticallyeffective amount of the composition of claim
 14. 23. The method of claim22, wherein the disorder resulting from elevated levels of COX-2 isangiogenesis, arthritis, asthma, bronchitis, menstrual cramps, prematurelabor, tendinitis, bursitis, skin-related condition, neoplasia,inflammatory processes in diseases, ophthalmic disorder, pulmonaryinflammation, central nervous system disorder, allergic rhinitis,respiratory distress syndrome, endotoxin shock syndrome,atherosclerosis, inflammation and/or microbial infection, cardiovasculardisorder, urinary and/or urological disorder, endothelial dysfunction,preservation of organs and tissues, inhibition of activation, adhesionand infiltration of neutrophils at the site of inflammation, orinhibition of platelet aggregation.
 24. The method of claim 23, whereinthe neoplasia is a brain cancer, a bone cancer, an epithelialcell-derived neoplasia (epithelial carcinoma), a basal cell carcinoma,an adenocarcinoma, a gastrointestinal cancer, a lip cancer, a mouthcancer, an esophageal cancer, a small bowel cancer, a stomach cancer, acolon cancer, a liver cancer, a bladder cancer, a pancreas cancer, anovary cancer, a cervical cancer, a lung cancer, a breast cancer, a skincancer, a squamus cell cancer, a basal cell cancer, a prostate cancer, arenal cell carcinoma, a cancerous tumor, a growth, a polyp, anadenomatous polyp, a familial adenomatous polyposis or a fibrosisresulting from radiation therapy.
 25. The method of claim 23, whereinthe central nervous system disorder is cortical dementias, Alzheimer'sdisease, vascular dementia, multi-infarct dementia, pre-senile dementia,alcoholic dementia, senile dementia, central nervous system damageresulting from stroke, ischemia or trauma.
 26. A method for inhibitingplatelet aggregation in a patient in need thereof comprisingadministering to the patient a therapeutically effective amount of thecomposition of claim
 14. 27. A composition comprising at least onecompound of claim 1 or a pharmaceutically acceptable salt thereof, andat least one compound that donates, transfers or releases nitric oxide,or induces the production of endogenous nitric oxide orendothelium-derived relaxing factor, or is a substrate for nitric oxidesynthase.
 28. The composition of claim 27 further comprising apharmaceutically acceptable carrier.
 29. The composition of claim 27,wherein the compound that donates, transfers, or releases nitric oxide,or induces the production of endogenous nitric oxide orendothelium-derived relaxing factor or is a substrate for nitric oxidesynthase is an S-nitrosothiol.
 30. The composition of claim 29, whereinthe S-nitrosothiol is S-nitroso-N-acetylcysteine, S-nitroso-captopril,S-nitroso-N-acetylpenicillamine, S-nitroso-homocysteine,S-nitroso-cysteine, S-nitroso-glutathione, orS-nitroso-cysteinyl-glycine.
 31. The composition of claim 29, whereinthe S-nitrosothiol is: (i) HS(C(R_(e))(R_(f)))_(m)SNO; (ii)ONS(C(R_(e))(R_(f)))_(m)R_(e); or (iii)H₂N—CH(CO₂H)—(CH₂)_(m)—C(O)NH—CH(CH₂SNO)—C(O)NH—CH₂—CO₂H; wherein m isan integer from 2 to 20; R_(e) and R_(f) are each independently ahydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy, anhydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring, acycloalkylalkyl, a heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino,an alkylamino, a dialkylamino, an arylamino, a diarylamino, analkylarylamino, an alkoxyhaloalkyl, a haloalkoxy, a sulfonic acid, asulfonic ester, an alkylsulfonic acid, an arylsulfonic acid, anarylalkoxy, an alkylthio, an arylthio, a cyano, an aminoalkyl, anaminoaryl, an aryl, an arylalkyl, a carboxamido, a alkylcarboxamido, anarylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylicacid, an arylcarboxylic acid, an alkylcarbonyl, an arylcarbonyl, anester, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylicester, a haloalkoxy, a sulfonarnido, an alkylsulfonamido, anarylsulfonamido, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfonyl,an arylsulfonyloxy, a urea, a nitro, —T—Q—, or—(C(R_(g))(R_(h)))_(k)—T—Q or R_(e) and R_(f) taken together are an oxo,a methanthial, a heterocyclic ring, a cycloalkyl group, an oxime, ahydrazone or a bridged cycloalkyl group; Q is —NO or —NO₂; and T isindependently a covalent bond, a carbonyl, an oxygen, —S(O)_(o)— or—N(R_(a))R_(i)—, wherein o is an integer from 0 to 2, R_(a) is a lonepair of electrons, a hydrogen or an alkyl group; R_(i) is a hydrogen, analkyl, an aryl, an alkylcarboxylic acid, an arylcarboxylic acid, analkylcarboxylic ester, an arylcarboxylic ester, an alkylcarboxamido, anarylcarboxamido, an alkylsulfinyl, an alkylsulfonyl, analkylsulfonyloxy, an arylsulfinyl, an arylsulfonyloxy, an arylsulfonyl,a sulfonamido, a carboxamido, a carboxylic ester, an aminoalkyl, anaminoaryl, —CH₂—C(T—Q)(R_(g))(R_(h)), or —(N₂O₂—)^(−M) ⁺, wherein M⁺ isan organic or inorganic cation; with the proviso that when R_(i) is—CH₂—C(T—Q)(R_(g))(R_(h)) or —(N₂O₂—)•M⁺; then “—T—Q” can be a hydrogen,an alkyl group, an alkoxyalkyl group, an aminoalkyl group, a hydroxygroup or an aryl group; and R_(g) and R_(h) at each occurrence areindependently R_(e).
 32. The composition of claim 27, wherein thecompound that donates, transfers, or releases nitric oxide, or inducesthe production of endogenous nitric oxide or endothelium-derivedrelaxing factor, or is a substrate for nitric oxide synthase isL-arginine, L-homoarginine, N-hydroxy-L-arginine, nitrosated L-arginine,nitrosylated L-arginine, nitrosated N-hydroxy-L-arginine, nitrosylatedN-hydroxy-L-arginine, nitrosated L-homoarginine, nitrosylatedL-homoarginine), citrulline, ornithine, glutamine, lysine, an arginaseinhibitor or a nitric oxide mediator.
 33. The composition of claim 27,wherein the compound that donates, transfers, or releases nitric oxide,or induces the production of endogenous nitric oxide orendothelium-derived relaxing factor, or is a substrate for nitric oxidesynthase is: (i) a compound that comprises at least one ON—O— or ON—N—group; (ii) a compound that comprises at least one O₂N—O—, O₂N—N— orO₂N—S— or group; (iii) a N-oxo-N-nitrosoamine having the formula:R^(1″)R^(2″)N—N(O—M⁺)—NO, wherein R^(1″) and R^(2″) are eachindependently a polypeptide, an amino acid, a sugar, an oligonucleotide,a straight or branched, saturated or unsaturated, aliphatic or aromatic,substituted or unsubstituted hydrocarbon, or a heterocyclic group, andM⁺ is an organic or inorganic cation.
 34. The composition of claim 33,wherein the compound comprising at least one ON—O— or ON—N— group is anON—O-polypeptide, an ON—N-polypeptide, an ON—O-amino acid, an ON—N-aminoacid, an ON—O-sugar, an ON—N-sugar, an ON—O-oligonucleotide, anON—N-oligonucleotide, a straight or branched, saturated or unsaturated,substituted or unsubstituted, aliphatic or aromatic ON—O-hydrocarbon, astraight or branched, saturated or unsaturated, substituted orunsubstituted, aliphatic or aromatic ON—N-hydrocarbon, anON—O-heterocyclic compound or an ON—N-heterocyclic compound.
 35. Thecomposition of claim 33, wherein compound comprising at least oneO₂N—O—, O₂N—N— or O₂N—S— group is an O₂N—O-polypeptide, anO₂N—N-polypeptide, an O₂N—S-polypeptide, an O₂N—O-amino acid,O₂N—N-amino acid, O₂N—S-amino acid, an O₂N—O-sugar, an O₂N—N-sugar,O₂N—S-sugar, an O₂N—O-oligonucleotide, an O₂N—N-oligonucleotide, anO₂N—S-oligonucleotide, a straight or branched, saturated or unsaturated,aliphatic or aromatic, substituted or unsubstituted O₂N—O-hydrocarbon, astraight or branched, saturated or unsaturated, aliphatic or aromatic,substituted or unsubstituted O₂N—N-hydrocarbon, a straight or branched,saturated or unsaturated, aliphatic or aromatic, substituted orunsubstituted O₂N—S-hydrocarbon, an O₂N—O-heterocyclic compound, anO₂N—N-heterocyclic compound or an O₂N—S-heterocyclic compound.
 36. Thecomposition of claim 37, further comprising at least one therapeuticagent.
 37. The composition of claim 36, wherein the therapeutic agent isa steroid, a nonsteroidal anti-inflammatory compound, a 5-lipoxygenase(5-LO) inhibitor, a leukotriene B₄ receptor antagonist, a leukotriene A₄hydrolase inhibitor, a 5-HT agonist, a HMG CoA inhibitor, a H₂antagonist, an antineoplastic agent, an antiplatelet agent, a thrombininhibitor, a thromboxane inhibitor, a decongestant, a diuretic, asedating or non-sedating anti-histamine, an inducible nitric oxidesynthase inhibitor, an opioid, an analgesic, a Helicobacter pyloriinhibitor, a proton pump inhibitor, an isoprostane inhibitor, or amixture of two or more thereof.
 38. A method for treating or reducinginflammation, pain or fever in a patient in need thereof comprisingadministering to the patient a therapeutically effective amount of thecomposition of claim 27 or
 36. 39. A method for treating agastrointestinal disorder, or improving the gastrointestinal propertiesof a COX-2 inhibitor in a patient in need thereof comprisingadministering to the patient a therapeutically effective amount of thecomposition of claim 27 or
 36. 40. The method of claim 39, wherein thegastrointestinal disorder is an inflammatory bowel disease, Crohn'sdisease, gastritis, irritable bowel syndrome, ulcerative colitis, apeptic ulcer, a stress ulcer, a bleeding ulcer, gastric hyperacidity,dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophagealreflux disease, a bacterial infection, short-bowel (anastomosis)syndrome, or a hypersecretory state associated with systemicmastocytosis or basophilic leukemia and hyperhistaminemia.
 41. A methodfor facilitating wound healing in a patient in need thereof comprisingadministering to the patient a therapeutically effective amount of thecomposition of claim 27 or
 36. 42. The method of claim 41, wherein thewound is an ulcer.
 43. A method for treating or reversing renal and/orrespiratory toxicity in a patient in need thereof comprisingadministering to the patient a therapeutically effective amount of thecomposition of claim 27 or
 36. 44. A method for treating a disorderresulting from elevated levels of COX-2 in a patient in need thereofcomprising administering to the patient a therapeutically effectiveamount of the composition of claim 27 or
 36. 45. The method of claim 44,wherein the disorder resulting from elevated levels of COX-2 isangiogenesis, arthritis, asthma, bronchitis, menstrual cramps, prematurelabor, tendinitis, bursitis, skin-related condition, neoplasia,inflammatory processes in diseases, ophthalmic disorder, pulmonaryinflammation, system disorder, allergic rhinitis, respiratory distresssyndrome, endotoxin shock syndrome, atherosclerosis, inflammation and/ormicrobial infection, cardiovascular disorder, urinary and/or urologicaldisorder, endothelial dysfunction, preservation of organs and tissues,inhibition of activation, adhesion and infiltration of neutrophils atthe site of inflammation, or inhibition of platelet aggregation.
 46. Themethod of claim 45, wherein the neoplasia is a brain cancer, a bonecancer, an epithelial cell-derived neoplasia (epithelial carcinoma), abasal cell carcinoma, an adenocarcinoma, a gastrointestinal cancer, alip cancer, a mouth cancer, an esophageal cancer, a small bowel cancer,a stomach cancer, a colon cancer, a liver cancer, a bladder cancer, apancreas cancer, an ovary cancer, a cervical cancer, a lung cancer, abreast cancer, a skin cancer, a squamus cell cancer, a basal cellcancer, a prostate cancer, a renal cell carcinoma, a cancerous tumor, agrowth, a polyp, an adenomatous polyp, a familial adenomatous polyposisor a fibrosis resulting from radiation therapy.
 47. The method of claim45, wherein the central nervous system disorder is cortical dementias,Alzheimer's disease, vascular dementia, multi-infarct dementia,pre-senile dementia, alcoholic dementia, senile dementia, centralnervous system damage resulting from stroke, ischemia or trauma.
 48. Amethod for inhibiting platelet aggregation in a patient in need thereofcomprising administering to the patient a therapeutically effectiveamount of the composition of claims 27 or
 36. 49. A kit comprising atleast one compound of claim 1 or a pharmaceutically acceptable saltthereof.
 50. The kit of claim 49, further comprising at least onecompound that donates, transfers or releases nitric oxide, induces theproduction of endogenous nitric oxide or endothelium-derived relaxingfactor, or is a substrate for nitric oxide synthase or at least onetherapeutic agent.
 51. The kit of claim 50, wherein the at least onecompound that donates, transfers or releases nitric oxide, induces theproduction of endogenous nitric oxide or endothelium-derived relaxingfactor, or is a substrate for nitric oxide synthase or the at least onetherapeutic agent are in the form of separate components in the kit orare in the form of a composition in the kit.
 52. A kit comprising thecomposition of claim 14, 27 or
 36. 53. The compound of claim 1, whereinthe compound of claim 1 is a nitrosated2(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate, anitrosylated 2(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate,a nitrosated and nitrosylated 2(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate or a pharmaceutically acceptable saltthereof.
 54. A compound selected from the group consisting of2-(2-(nitroxy)ethylthio)ethyl2(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate,2-(2-(nitroxy)ethoxy)ethyl2(2((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate,3-((nitroxy)methylphenyl)2(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate,2,3-bis(nitroxy)propyl2(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate,6-(nitroxy)-4,8-dioxabicyclo(3.3.0)oct-2-yl2-(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate,2-((2-(nitroxy)ethyl)sulfonyl) ethyl2(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate,2-(4-(2-nitrooxyl)ethyl) piperazinyl)-2-oxoethyl2-(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate,2,3-bis(nitroxy)-4-(2-(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetyloxy)butyl2-(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate,2-(2-(hydroxyethylthio)ethyl2(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate,2-(2-(hydroxyethoxy)ethyl2(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate,3-(hydroxymethylphenyl)2(2-((2chloro-6-fluorophenyl)amino)5-methylphenyl)acetate,2,3-dihydroxypropyl2(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate,6-hydroxy-4,8-dioxabicyclo(3.3.0)oct-2-yl2(2-((2chloro-6-fluorophenyl)amino)5-methylphenyl)acetate,2-((2-hydroxyethyl)sulfonyl) ethyl2(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate,2-(4-(2-hydroxyethyl)piperazinyl)-2-oxoethyl2-(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetate,4-(2-(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetoxy)-2,3-dihydroxybutyl-2-(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)acetyloxy)butylacetate, or a pharmaceutically acceptable salt thereof.
 55. Acomposition comprising at least one compound of claim 54 and apharmaceutically acceptable carrier.
 56. A kit comprising at least onecompound of claim 54 or a pharmaceutically acceptable salt thereof. 57.A composition comprising at least one parent COX-2 inhibitor of Formula(I), or a pharmaceutically acceptable salt thereof, and at least onecompound that donates, transfers or releases nitric oxide, or inducesthe production of endogenous nitric oxide or endotheliumderived relaxingfactor, or is a substrate for nitric oxide synthase.
 58. The compositionof claim 57 further comprising a pharmaceutically acceptable carrier.59. The composition of claim 57, wherein the parent COX-2 inhibitor ofFormula (I) is 2(2-((2-chloro-6-fluorophenyl)amino)5-methylphenyl)aceticacid.
 60. The composition of claim 57, wherein the compound thatdonates, transfers, or releases nitric oxide, or induces the productionof endogenous nitric oxide or endothelium-derived relaxing factor or isa substrate for nitric oxide synthase is an S-nitrosothiol.
 61. Thecomposition of claim 60, wherein the S-nitrosothiol isS-nitroso-N-acetylcysteine, S-nitroso-captopril,S-nitroso-N-acetylpenicillamine, S-nitroso-homocysteine,S-nitroso-cysteine, S-nitroso-glutathione, orS-nitroso-cysteinyl-glycine.
 62. The composition of claim 60, whereinthe S-nitrosothiol is: (i) HS(C(R_(e))(R_(f)))_(m)SNO; (ii)ONS(C(R_(e))(R_(f)))_(m)R_(e); or (iii)H₂N—CH(CO₂H)—(CH₂)_(m)—C(O)NH—CH(CH₂SNO)—C(O)NH—CH₂—CO₂H; wherein m isan integer from 2 to 20; R_(e) and R_(f) are each independently ahydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy, anhydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring, acycloalkylalkyl, a heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino,an alkylamino, a dialkylamino, an arylamino, a diarylamino, analkylarylamino, an alkoxyhaloalkyl, a haloalkoxy, a sulfonic acid, asulfonic ester, an alkylsulfonic acid, an arylsulfonic acid, anarylalkoxy, an alkylthio, an arylthio, a cyano, an aminoalkyl, anaminoaryl, an aryl, an arylalkyl, a carboxamido, a alkylcarboxamido, anarylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylicacid, an arylcarboxylic acid, an alkylcarbonyl, an arylcarbonyl, anester, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylicester, a haloalkoxy, a sulfonamido, an alkylsulfonamido, anarylsulfonamido, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfonyl,an arylsulfonyloxy, a urea, a nitro, —T—Q—, or—(C(R_(g))(R_(h)))_(k)—T—Q or R_(e) and R_(f) taken together are an oxo,a methanthial, a heterocyclic ring, a cycloalkyl group, an oxime, ahydrazone or a bridged cycloalkyl group; Q is —NO or —NO₂; and T isindependently a covalent bond, a carbonyl, an oxygen, —S(O)_(o)— or—N(R_(a))R_(i)—, wherein o is an integer from 0 to 2, R_(a) is a lonepair of electrons, a hydrogen or an alkyl group; R_(i) is a hydrogen, analkyl, an aryl, an alkylcarboxylic acid, an arylcarboxylic acid, analkylcarboxylic ester, an arylcarboxylic ester, an alkylcarboxamido, anarylcarboxamido, an alkylsulfinyl, an alkylsulfonyl, analkylsulfonyloxy, an arylsulfinyl, an arylsulfonyloxy, an arylsulfonyl,a sulfonamido, a carboxamido, a carboxylic ester, an aminoalkyl, anaminoaryl, —CH₂—C(T—Q)(R_(g))(R_(h)), or —(N₂O₂—)⁻•M⁺, wherein M⁺ is anorganic or inorganic cation; with the proviso that when R_(i) is—CH₂—C(T—Q)(R_(g))(R_(h)) or —(N₂O₂—)•M⁺; then “—T—Q” can be a hydrogen,an alkyl group, an alkoxyalkyl group, an aminoalkyl group, a hydroxygroup or an aryl group; and R_(g) and R_(h) at each occurrence areindependently R_(e).
 63. The composition of claim 57, wherein thecompound that donates, transfers, or releases nitric oxide, or inducesthe production of endogenous nitric oxide or endothelium-derivedrelaxing factor, or is a substrate for nitric oxide synthase isL-arginine, L-homoarginine, N-hydroxy-L-arginine, nitrosated L-arginine,nitrosylated L-arginine, nitrosated N-hydroxy-L-arginine, nitrosylatedN-hydroxy-L-arginine, nitrosated L-homoarginine, nitrosylatedL-homoarginine), citrulline, ornithine, glutamine, lysine, an arginaseinhibitor or a nitric oxide mediator.
 64. The composition of claim 57,wherein the compound that donates, transfers, or releases nitric oxide,or induces the production of endogenous nitric oxide orendothelium-derived relaxing factor, or is a substrate for nitric oxidesynthase is: (i) a compound that comprises at least one ON—O— or ON—N—group; (ii) a compound that comprises at least one O₂N—O—, O₂N—N— orO₂N—S— or group; (iii) a N-oxo-N-nitrosoamine having the formula:R^(1″)R^(2″)N—N(O—M⁺)—NO, wherein R^(1″) and R^(2″) are eachindependently a polypeptide, an amino acid, a sugar, an oligonucleotide,a straight or branched, saturated or unsaturated, aliphatic or aromatic,substituted or unsubstituted hydrocarbon, or a heterocyclic group, andM⁺ is an organic or inorganic cation.
 65. The composition of claim 64,wherein the compound comprising at least one ON—O— or ON—N— group is anON—O-polypeptide, an ON—N-polypeptide, an ON—O-amino acid, an ON—N-aminoacid, an ON—O-sugar, an ON—N-sugar, an ON—O-oligonucleotide, anON—N-oligonucleotide, a straight or branched, saturated or unsaturated,substituted or unsubstituted, aliphatic or aromatic ON—O-hydrocarbon, astraight or branched, saturated or unsaturated, substituted orunsubstituted, aliphatic or aromatic ON—N-hydrocarbon, anON—O-heterocyclic compound or an ON—N-heterocyclic compound.
 66. Thecomposition of claim 64, wherein compound comprising at least oneO₂N—O—, O₂N—N— or O₂N—S— group is an O₂N—O-polypeptide, anO₂N—N-polypeptide, an O₂N—S-polypeptide, an O₂N—O-amino acid,O₂N—N-amino acid, O₂N—S-amino acid, an O₂N—O-sugar, an O₂N—N-sugar,O₂N—S-sugar, an O₂N—O-oligonucleotide, an O₂N—N-oligonucleotide, anO₂N—S-oligonucleotide, a straight or branched, saturated or unsaturated,aliphatic or aromatic, substituted or unsubstituted O₂N—O-hydrocarbon, astraight or branched, saturated or unsaturated, aliphatic or aromatic,substituted or unsubstituted O₂N—N-hydrocarbon, a straight or branched,saturated or unsaturated, aliphatic or aromatic, substituted orunsubstituted O₂N—S-hydrocarbon, an O₂N—O-heterocyclic compound, anO₂N—N-heterocyclic compound or an O₂N—S-heterocyclic compound.
 67. Thecomposition of claim 57, further comprising at least one therapeuticagent.
 68. The composition of claim 67, wherein the therapeutic agent isa steroid, a nonsteroidal anti-inflammatory compound, a 5-lipoxygenase(5-LO) inhibitor, a leukotriene B₄ receptor antagonist, a leukotriene A₄hydrolase inhibitor, a 5-HT agonist, a HMG CoA inhibitor, a H₂antagonist, an antineoplastic agent, an antiplatelet agent, a thrombininhibitor, a thromboxane inhibitor, a decongestant, a diuretic, asedating or non-sedating anti-histamine, an inducible nitric oxidesynthase inhibitor, an opioid, an analgesic, a Helicobacter pyloriinhibitor, a proton pump inhibitor, an isoprostane inhibitor, or amixture of two or more thereof.
 69. A method for treating or reducinginflammation, pain or fever in a patient in need thereof comprisingadministering to the patient a therapeutically effective amount of thecomposition of claim 57 or
 67. 70. A method for treating agastrointestinal disorder, or improving the gastrointestinal propertiesof a COX-2 inhibitor in a patient in need thereof comprisingadministering to the patient a therapeutically effective amount of thecomposition of claim 57 or
 67. 71. The method of claim 70, wherein thegastrointestinal disorder is an inflammatory bowel disease, Crohn'sdisease, gastritis, irritable bowel syndrome, ulcerative colitis, apeptic ulcer, a stress ulcer, a bleeding ulcer, gastric hyperacidity,dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophagealreflux disease, a bacterial infection, short-bowel (anastomosis)syndrome, or a hypersecretory state associated with systemicmastocytosis or basophilic leukemia and hyperhistaminemia.
 72. A methodfor facilitating wound healing in a patient in need thereof comprisingadministering to the patient a therapeutically effective amount of thecomposition of claim 57 or
 67. 73. The method of claim 72, wherein thewound is an ulcer.
 74. A method for treating or reversing renal and/orrespiratory toxicity in a patient in need thereof comprisingadministering to the patient a therapeutically effective amount of thecomposition of claim 57 or
 67. 75. A method for treating a disorderresulting from elevated levels of COX-2 in a patient in need thereofcomprising administering to the patient a therapeutically effectiveamount of the composition of claim 57 or
 67. 76. The method of claim 75,wherein the disorder resulting from elevated levels of COX-2 isangiogenesis, arthritis, asthma, bronchitis, menstrual cramps, prematurelabor, tendinitis, bursitis, skin-related condition, neoplasia,inflammatory processes in diseases, ophthalmic disorder, pulmonaryinflammation, central nervous system disorder, allergic rhinitis,respiratory distress syndrome, endotoxin shock syndrome,atherosclerosis, inflammation and/or microbial infection, cardiovasculardisorder, urinary and/or urological disorder, endothelial dysfunction,preservation of organs and tissues, inhibition of activation, adhesionand infiltration of neutrophils at the site of inflammation, orinhibition of platelet aggregation.
 77. The method of claim 76, whereinthe neoplasia is a brain cancer, a bone cancer, an epithelialcell-derived neoplasia (epithelial carcinoma), a basal cell carcinoma,an adenocarcinoma, a gastrointestinal cancer, a lip cancer, a mouthcancer, an esophageal cancer, a small bowel cancer, a stomach cancer, acolon cancer, a liver cancer, a bladder cancer, a pancreas cancer, anovary cancer, a cervical cancer, a lung cancer, a breast cancer, a skincancer, a squamus cell cancer, a basal cell cancer, a prostate cancer, arenal cell carcinoma, a cancerous tumor, a growth, a polyp, anadenomatous polyp, a familial adenomatous polyposis or a fibrosisresulting from radiation therapy.
 78. The method of claim 76, whereinthe central nervous system disorder is cortical dementias, Alzheimer'sdisease, vascular dementia, multi-infarct dementia, pre-senile dementia,alcoholic dementia, senile dementia, central nervous system damageresulting from stroke, ischeniia or trauma.
 79. A method for inhibitingplatelet aggregation in a patient in need thereof comprisingadministering to the patient a therapeutically effective amount of thecomposition of claims 57 or
 67. 80. A kit comprising at least one parentCOX-2 inhibitor and at least one compound that donates, transfers, orreleases nitric oxide, or induces the production of endogenous nitricoxide or endothelium-derived relaxing factor or is a substrate fornitric oxide synthase, or a pharmaceutically acceptable salt thereof, orat least one therapeutic agent.
 81. The kit of claim 80, wherein the atleast one parent COX-2 inhibitor and compound that donates, transfers orreleases nitric oxide, induces the production of endogenous nitric oxideor endothelium-derived relaxing factor, or is a substrate for nitricoxide synthase or the at least one therapeutic agent are in the form ofseparate components in the kit or are in the form of a composition inthe kit.